The perks that I'll pick regardless of character build will be: Educated, Comprehension, Cyborg, Scrounger, Fortune Finder, Strong Back, Better Criticals, Action Boy/Girl and Mysterious Stranger. The rest of the perks will depend on my character's specialization. If I'm using any form of guns, I'll be picking up Sniper. Specialists in melee and explosives won't need bonuses to hit% in VATS, since they can't target specific limbs and from my experience, as long as you're in range the hit% is 95.
Roleplay options - Child at Heart, Ladykiller/Black Widow. The +10% to damage against the opposite sex is cool, but not really useful as SuperMutants, organic and robotic monsters are asexual.
Explosives - all 3 ranks of Demolition Expert.
Melee - Pyromaniac + Ninja. The Shiskabab is the strongest melee weapon and gets my personal vote as the coolest weapon in Fallout 3. At base it is 40 with 100 Melee and in 100% condition, and Pyromaniac augments it further into a whopping 60 points of damage. The only problem is finding enough motorcycle parts to last you a good 20~40 hours if you don't have a secondary/tertiary weapon specialization.
Big Guns - I'll go with Pyromaniac for Flame Thrower's increased power, as well as Action Boy/Girl and Grim Repear's Sprint as heavy weapons take up a shit load of APs to use. I'm not sure if Commando affects Big Guns, and until I'm sure I'm not taking the risk of wasting one perk.
Energy Weapons/Small Guns - definitely Sniper + Commando. The A3-21 is governed by Energy Weapons; is both a rifle and can easily decapitate most humanoid foes. Despite being energy weapons, the Alien Blaster and Gatling Laser are governed by Small Guns and Big Guns respectively. The huge array of uniques in Small Guns are mostly 2-handed rifles as well - The Terrible Shotgun, Lincoln's Repeater, Xuanlong's Rifle etc.
Unarmed - Ninja + Paralyzing Palm + Iron Fist.
Borderline useful perks. I consider these to be mildly useful, and should only be taken when there's nothing else useful on the option list during level up:
- Finesse/Concentrated Fire/Bloody Mess. The bonuses aren't really worth it. +5% to critical is the better choice, since if you've scored a critical to disarm/cripple/decapitate you no longer need the bonuses to hit normally.
- Animal Friend. This is another roleplaying perk, because killing Yao Guai isn't too hard from level 8 onwards, and I would rather take their meat and kill myself than let them do the work for me. Exp..exp~
- Entomologist. You don't really encounter a whole lot of Radscorpions, and even the giant variants go down easily without this perk. Radroaches are weak, and Fire Ants also require little effort to deal with. I'm not sure if Mirelurks are affected by this perk, but no biggie, aim for their face and they go down fast.
- Master Trader. Only useful if you buy a lot. I don't, all my parts and ammo are loot picked up from the Wastelands. I spend money only on followers who need caps in exchange for services, and schematics. I'm not sure if it affects the selling price of items..
Perks I'll avoid completely:
- Rad Resistance. Biosuits + decent Medicine skill + Rad-X, or even power armors + Rad-X is sufficient.
- Lead Belly. Pop a Rad-X before consuming food.
- Gun Slinger. The only pistol worth a damn is the Alien Blaster, and unfortunately its ammo is rare. Its high critical rate is already awesome without the need to add a bonus to hit.
- Nerd Rage. Bonuses only kick in when your life bar is < 20%. Unless you're going for a challenge which means constantly living on the edge, I won't recommend this for players seeking a safe and stable build in their plays. Further, DR is capped at 85, and there're 3 ways to improve base DR. The Oasis quest has an outcome that gives + 10%, Cyborg gives + 10% and Toughness give + 10%. That's 30% base and combined with armors that give 30~40 DR, it is almost close to the cap of 85. Besides, cover does matter in this game, so you shouldn't be taking that much damage anyway.
- LawBringer/Contract Killer. Never tested this myself, although 10 caps per finger is a complete waste of time when Fortune Finder constantly gives you 30~80 caps from each random container.
- Impartial Mediation. With Naughty Nightware and Button's Wig, that's +20 to Speech right there; stacked with Speech Bobblehead and we've 30 free points in Speech.
- Here and Now. lv cap is at 20, period. You should only be taking this if you plan on speed runs and have no intention of finishing that play at 20.
- Fast Metabolism/Life Giver. Medicine + Stimpaks or Rad-X > consume food. Why is there a need for extra health?
- Adamantium Skeleton. Find a bed to rest/consume Stimpaks. Problem solved.
- Chemist/Chem Resistance. I've never come close to a situation in Fallout 3 where the heavy usage of drugs is mandatory, as opposed to optional.
- Inflitrator/Computer Whiz - After 3 failed attempts, exit and try again.
- Mister Sandman. Look, most of the foes in this game won't be sleeping when you face them, you can count on that. If you must murder an isolated individual without pissing off an entire town, do it when everyone is sleeping, and if you do get caught, just run and zone out of the town. The residents will forgive you after a few days.
- Robotics Expert. One major caveat being when you managed to shut down a robot by sneaking, it does not give you any ammo. In a shut down state, you can't use VATS to target, negating all +hit/critical% bonuses and the possibility of OHKO from Mysterious Stranger. In other words, the amount of ammo you get back by manually targeting a robot is almost the same (or more) spent killing it. The +25% to damage isn't really significant against Sentry type robots.
- Cannibal. Useless you like to roleplay. There are plenty of ways to restore health in Fallout 3.
- Explorer. I have access to 4 maps of Fallout 3 and I enjoy the initial leisure stroll needed to discover a location for future fast travels.
- Night Person/Solar Powered - SPECIAL is capped at 10, and really more health bonuses? This is getting old, but yes, beds/Stimpaks/Rad-X + food.
Skillpoints perks: should you be using them? Depends on your play-style. I've addressed this before. If you plan to locate all skillbooks you get 50 free points per skill, and eXistor mentioned that bobbleheads also give +10 skill points to each corresponding skill. They are just an option for you to get more skill points at the expense of perks, so if you find that you have an extra perk slot or 2, but need skillpoints in 2 sets of skills feel free to go ahead and pump them. I view this as a failsafe against "bad" builds, for Fallout 3 does not allow you to undo your investments in skill points and perks (Etrian Odyssey/Fable II). Think of it as a safety net to encourage pushing through with your current build without having to start all over from scratch.