I typically mix and match. I start with guns in the early game, and then as the game progresses I move into energy weapons.
From the start, I like to follow this progression:
- A generic pistol or rifle (ie, the one you get from the tutorial, Courier's Stash, or a 9/10mm from early gang fights)
- That Gun - you can buy it early on in Novac. It's a 5.56 revolver (so it counts for many GRA challenges), it packs a major punch, and it's easy to get early on.
- Ratslayer - from the Broc Flower cave, it can be tricky to kill the rats in there, but it is a mainstay weapon of my arsenal for most of the game - silent, long distance, night vision scope, light weight, etc
If you've got the GRA expansion, Sleepytyme is worth buying from the Gun Runner's Kiosk - it's a silenced 10mm SMG that packs a huge punch in close range or against multiple targets. If you have Lonesome Road, you can find Riot Shotguns pretty easily on Marked Men (although they exist outside of the expansion as well) which are similarly powerful up close when the fecal matter is impacting the rotating blades.
Once I make it to level 20 or so, I typically have high enough guns stat that I can drop points in energy weapons, so I'll grab:
- Q-35 Matter Modulator - low requirements (25 energy weapons) and it packs a pretty decent punch.
- YCS/186 - hard hitting, but requires a very high energy weapons skill, unfortunately.
But honestly, I tend to prefer the Holorifle - it packs a major punch, does damage over time, and is one of the more powerful weapons in the game. The only downside is that you can only repair it with Weapon Repair Kits, so make sure that you max out your chips in Dead Money and find the Weapon Repair Kit code for the vending machine. That way, you can return to the abandoned BoS bunker for more kits if you need them. (protip: get the stimpak code too!)
By the higher levels, the Holorifle was my go-to gun for direct engagements, with the Ratslayer backing me up against soft targets or in stealth. Sleepytyme or the Riot Shotgun was a close third, being useful in close quarters when the long reload and bad hipfire accuracy of the rifles was of concern.
Some weapons I can say aren't worth the trouble:
- LAER - does heavy damage against robots, but durability wise it's terrible!
- Sonic Emitter - just kind of a meh weapon overall.
- Pew Pew - you get this for finishing the Sunset Sarsaparilla side quest, and it's powerful, but a little ammo-hog and a pain to aim
- .45 Auto - Honest Hearts is littered with these, but I didn't find them to be terribly useful.
- Gobi Campaign Scout Rifle - I used to swear by this weapon, but I just don't like it much anymore. I frequently will take Ratslayer instead, if I've got a good energy rifle that can fill this "heavy damage/hard target" slot. The other downside is that you have to pick a "very hard" lock to get it.
- Heavy weapons of pretty much any type - for the weight, you can carry stuff that's quite a bit more powerful, in my opinion.
I went out of my way to collect a few of these, and I was sorely disappointed.
Perk wise, I can say these were more or less essential:
- Jury Rigging - get this ASAP, it's no good for the Holorifle, but being able to repair your gear with anything you come across is super helpful.
- Weapon Handling - for low-STR builds, this is a must.
- Rapid Reload - the Holorifle in particular takes a while to reload
- Hand Loader - I kind of can go either way on this perk, but it is quite a bit better with the ED-E reloading bench "upgrade" that you get from having Lonesome Road installed.
Beyond that, it kind of depends on what you're packing. Rifles and 2-handed guns tend to be far more powerful and useful in the late game, so I'd focus on perks that boost those, like Commando and Sniper, over perks like Gunslinger or Run 'n Gun, for instance.
Also, if you've got all 4 expansions, you've got major amounts of skill and perk choices, so don't fret - chances are you'll have more than a few levels where you just don't have anything interesting to pick. You'll probably end up with quite a few "junk" skill picks as a result.