Depends on the pack.
My old Kelty carries very nicely with a 4-5/8" or 5.5" barreled Ruger single action in a (Uncle Mike's) shoulder holster under a jacket. I set it up so the bottom of the jacket and the pack straps really control the gun, not so much the holster straps.
I actually prefer putting the gun in the top compartment with the cinch slightly loose. I lay it in there with the muzzle to the left with the gun on it's side such that the butt is nearer to me. I can reach up behind my head and draw reasonably quickly. Gun is out of the weather, out of sight, out of my probably sweaty armpit, and quite accessible.
With my pack frame (Cabela's alaska guide) there's a gap behind my right hip where I can carry that same gun pretty comfortably between myself and the padded waist belt in a conventional holster. (This also works with the Kelty depending on load.)
I have not found a good solution for an internal frame pack like the Badlands 2200 I bought last fall. With a long barreled single action I can put the gun muzzle-down between the 2 layers of the waist band. Gotta keep an eye on it so it doesn't try to escape, though, and I have no solution at all for a short barreled gun. With a cross-chest stablizer strap and more centered shoulder pads, the shoulder holster does not work well for me.
Tom