I've been playing Senna almost exclusively for a while now and I main Support role. Now that I'm playing League a bit less often I find myself one-tricking her in Normals since I end most games with S+ and doing top damage (often by a substaintial margin).

I've tried both First Strike and Dark Harvest keystones for extended periods of time each.

First Strike feels very situational - it depends a lot on the enemy team failing to punish you when you go in and having less range against you. Never take it going into a Miss Fortune or a Lux for example. Furthermore, the pressure to utilize First Strike effectively means you feel pressured to engage when you shouldn't and stay in longer than you should. This is, of course, mostly a psychological matter. Having said that, even if you don't find yourself making bad calls because of First Strike, you will benefit more from Fleet Footwork.

Dark Harvest is good but less reliable. You need to be consistently farming stacks and getting takedowns and even then it doesn't have any particlar synergy with Senna's kit. Against weaker enemies, triggering your passive can sometimes bring them to 50% hp and then hitting them with another basic will collect a stack but that's it.

Can't stress enough how strong Fleet Footwork is on Senna. I only recently picked it up since I had never run fleet before and it didn't sound all that good.. but it is! I often end games having healed up 5k+ just from fleet. Then there's the movement speed which lets you get in and out of a poke rotation easily or fire a Q through a minion and close the distance to fire a basic attack for the passive proc. Since your Q slows enemies and you get speed at the same time, you can escape from any chase just about. Not to mention, if you are low health you can use your Q to heal off the enemy from a very safe distance. As a bonus, Senna's Q only triggers on-hit for champions and towers so if you miss you won't end up resetting your fleet footwork stacks.

Minor Runes

Presence of Mind is a no-brainer. It means you never have to worry about mana (unless you are not poking - but you should be!).

Alacrity since none of the other legends offer any more value and the attack speed will still be useful.

Cut Down since Senna doesn't build health so it will see some benefit against most opponents and more against bruisers and tanks.

Secondary Rune Tree

Ghost Poro gives some extra stat and a lot more vision. It's a very satisfying pick on any support.

The new Treasure Hunter rune is good gold value and gets you to full build faster. Sadly Treasure Hunter provides no value after you are full build but it still beats other rune choices in my opinion.

As an alternative, Magical Footwear and Approach Velocity are also good picks but you don't really need the speed from Approach Velocity and the gold value from Magical Footwear is less than Treasure Hunter.

When in the ADC role, make sure you kill only melee minions and cannons. Don't overdo it on the melee minions either since you don't want to hit the minion cap and get less gold from cannons.

Eclipse

I alwways rush Serrated Dirk into Eclipse. Dirk gives a nice early game boost to damage and healing. Eclipse is a very strong item for Senna. Firstly, it has Lethality making it also boost your healing and damage against non-tanks. Secondly, it's passive effect syngergizes very well with Senna's Q+Basic combo which is her bread-and-butter. Lastly the omnivamp is not to be underestimated and it also triggers off souls when you grab them! The armour penetration mythic passive is also a very welcome stat.

Berserker's Greaves

Many builds suggest Boots of Swiftness due to Senna's attack speed multiplier being only 0.3 (she gets less than half as much value from attack speed as other champions). I, however, have found that the added attack speed is still very impactful. Especially when proccing your passive on multiple targets or claiming multiple souls.

The Collector

This item has both crit and lethality while not wasting stat value on attack speed. This item is tailor made to suit senna. The only reason it gets switched out in the other builds on this page is that every other item is irreplaceable. If vision is not a concern and you are building Lord Dominik's Regards, you may choose to build The Collector instead of a Wardstone.

Infinity Edge

This item is undeniably more damage output than Guinsoo's Rageblade on Senna no matter what you build due to her slower attack speed and bigger damage hits (even with her reduced crit multiplier). Since Senna is practically guaranteed to hit 100% crit rate (due to her passive) you should build this on any build.

Vigilent Wardstone

This item (upgraded from Watchful Wardstone) is an insanely powerful vision item, letting you have 2 concurrent vision wards and 4 concurrent stealth wards up at a time. Normally this comes at the cost of a lot of stat but since Senna's base attack damage is always 50, almost all her AD is Bonus AD which this item boosts by 12%. This makes Senna one of the few champions that synergizes especially well with this item. Cho'Gath and Veigar are other ones as an example. It's still not going to be as much stat as another AD item, but the vision is worth losing a bit of stat.

Having said all that

Senna is one of the most well rounded champions in the game as far as stat priorities go. As a result, any reasonable ADC build will work on her. Divine Sunderere? Yes. Kraken Slayer? Yes. Duskblade? Yes. Crit Build? Yes. Lethality Build? Yes. etc etc

Having spend extended periods of time with each build in my quest for the superior one I started with Kraken, converted to Lethality and finally landed on this hybrid build. I strongly believe this build is the ultimate fusion of all of those builds.

Threats

I always ban Brand and given that, I've never had an enemy lane give me grief. Senna is so strong and has so much range that it's really quite oppressive.

You may have to play more carefully around ranged poke supports like Xerath or Seraphine but you shouldn't have any significant issues.

The biggest threat to a Senna lane is pushing your lane up too hard and then getting the enemy jungler and/or mid laner making your life hard.

The next biggest threat is if you play too aggressively and end up so far behind on HP or momentum that you cannot contest the lane effectively from that point on.

Syngergies

Senna works well with most bot laners, especially those that can poke with her since short range or defensive bot laners will result in a 1v2 every time you go in to harass. I play Senna very aggressively in lane so laners like Kai'Sa do not work well with my playstyle.

Senna is also one of the few supports that can provide enough peel for a Yasuo bot to farm in peace.

Laning Phase

Your core loop in laning phase will be to get as many Auto+Q or Q+Auto combos off as you can. If the enemy is especially passive then some Auto+Auto combos will also be possible.

Q+Auto combo involves hitting the enemy with your Q either directly or by aiming it through a minion. Once that's done you use the speed boost from Fleet Footwork to close the distance and fire a basic attack to trigger your passive (and get a stack).

Auto+Q combo should be used if you are in basic attack range of the enemy. The reason for this is that firing your Q after your Auto has less delay and slightly better targetting range than vice versa (although both technically have the same range).

Gaining stacks and poking the enemy through this method is the key to a successful lane. If you have to play defensively, use minions to hit the enemy with Q to get your support item gold.

You should rarely use Q to heal your ADC in lane. Only do this if they are low and the enemy is not around. If they get low they should go back since your Q needs to be saved for your poking combos.

Be aware that auto attacking minions will consume your Fleet Footwork which means less movement speed and sustain when you need it.

If you have a roam or gank coming in, use your W (root) and then E (speed) to get out easily. You should rarely lose someone to ganks if you have vision up and aren't pushed at bad times.

Out of Laning Phase

Make sure you don't push too far alone. You can use your W to avoid an unwinnable 1v1 but if there's more than one of them you will be in trouble.

Remember that Fleet Footwork out of laning phase heals for a lot so if there are no enemies around (e.g. your team just won a team fight), feel free to push a tower when low since it will heal you right up.

Your Q isn't an auto-attack reset but it also doens't delay your auto attacks. What this means is you can weave Auto+Q+Auto to maximise your tower damage throughput.

Team Fights

In team fights you have the following priority for your targetting:

1. Enemies being attacked by allied melee champions. If you Q the enemy, in addition to dealing damage, your allies will be healed since the heal hitbox is larger than the damage hitbox.
2. Squishy enemies (not tank nor bruiser). These are anyway priority targets due to their higher damage output/support abilities. Depending on how well you did in laning phase, you'll be able to heavily damage squishy enemies just with your first two hits.
3. Anyone else.

As with laning phase, you do not want to use your Q to heal since it's damage and slow and combo potential are incredibly powerful.

Fasting/Post-Laning Phase Farming

As is standard for supports you have a minion cap. As a result you will want to only kill melee and cannon minions and if you are pushing a lane, aim to only weaken caster minions.

The same goes for laning phase if your ADC has to go back - only last hit melee and cannon, ignore casters.