I'm trying to limit myself to three weapons (and only two long arms, tops). Most of the reason for the preference is RP/character related. Right now, I have a varmint rifle (and am dying to find a scope), a cowboy repeater, and a 10mm. My rationale is as follows...
The varmint rifle is for sniping, plain and simple. Eventually, I will trick it out with the silencer and scope. I don't anticipate replacing it until I get a sniper rifle (the only other sniping weapon with a silencer option, right?)
The Cowboy repeater is for field combat, usually outside of VATS. Often times, when sniping, if my position is revealed, I have some time before they close the distance, or they maintain position and we're in a firefight. It's pretty accurate, though I hate the sights on it. The fat circular rear sight is more of a hindrance than anything. I would prefer something less obtrusive, but it has some seemingly cool mods and does decent single shot damage.
Finally, the 10mm is a backup piece, though I've used it instead of the Cowboy Repeater in quite a few situations just because I like the sights better. I almost went with the 10mm SMG, but I'm sure that like most FO games, shotguns and smgs just go splat against targets with decent armor (not that the pistol wouldn't). Also, I figured it being an improved holdout weapon gave it an edge over the SMG. I like the idea of always being armed, even though it will probably rarely be of benefit. The silencer is another plus. In fact, I think it's probably the most powerful non-DLC holdout weapon. I'm planning on a high Sneak, Silent Running, and Better Criticals, so I expect to be able to do a lot of close range sneak criticals. Lastly, I really don't want to be carrying around a lot of big guns. I think two long arms and a smaller weapon should be sufficient. Actually, I'd like to do just a single long arm and a single backup weapon, but I can't think of a combo that really has me covered.
So, these are the bases I'm trying to cover with my selection. I'm thinking of replacing the Cowboy repeater with an un-scoped hunting rifle when I come across one. It's more damage per shot, and probably has better sights. As for the 10mm, I don't know anything that would be a suitable replacement, though I expect it would be near useless by late game. Maybe give up the ghost on the silencer and go with a .44 mag?
Anyway, I'm open to tips, though. Got any?