Honestly? Depending on what mods you plan to play. Personally I found myself going down one of two routes.
The Gunslinging Merc- Pretty standard run, and my personal fave. Do whatever lines your pockets with more caps or makes your life easier and only use lead based guns, melee and hand to hand. Sadly this does rule out most explosive and energy weapons, but thats a small price to pay at the end of the day. Your karma is your choice, but like I said, even with good karma your choice was to be whatever made your life easier. Companions should fit to your gunslingers personality. After all, some teenage lover trouble aint your problem unless theres something in it for you. Only trouble with this run is that no matter what your gonna have to pick a side in the end, so try not to burn all your bridges befor hand.
The Mad Scientist - So we are hitting the opposite run with this guy. No physical attacking, no lead based guns, and bring as much help as humanly possible. This run requires little to no physical strenght but all the know how in the land. You use only energy weapons or flamers. Once again, Karma is optional, but I would suggest evil since you are gonna be only focusing on what benefits you and Science in the end. Burn(or melt) as many bridges as you like here, just remember that if you cant make friends, CREATE MINIONS! (insert evil laugh). This run focuses more on science medicine and energy weapons.