This is coming from a novice so you may want to take this with a grain of salt. We cannot hunt big game with rifles here so until this fall (first western hunt) my experience is limited to what I have been able to do on groundhogs and crows in the past 4 years of LR shooting/hunting.
I do all load development at no less than 450yd, any closer and a ladder test starts to get pretty cluttered. This gives me a load that will produce the best long range accuracy because, as others have stated, tiny groups don't matter as much at 2-300yd. Both my rifles regularly shoot .75MOA or less at 200yds but often shoot better groups at longer distances (best to-date is 3 shots into 1.5" at 585yd, but I would never lead anyone to believe I could replicate that group). .75MOA is sufficient for my skill level and comfortable hunting distances.
I also do all my practice and load development of a bipod and rear bag to simulate field conditions. I have tried shooting off a bench but usually shoot better off a bipod (probably because I have little to no experience shooting off a benchrest).
I zero my rifles at 200yds simply because it's a nice round number and I don't really care if I'm off by an inch and a half inside of 200yd on big game animals (blackbirds in the swamp are a different story).
I have a 12" round gong that I set up in the field and shoot from various positions much like davkrat. If I cannot consistently land a first round cold bore shot on that gong then I will not shoot at an animal at that distance (with the exception of groundhogs and crows). You must also consider the size of the vitals of the animal you are pursuing. I will be going after pronghorn this fall so realistically I must be able to hit within 4" of center (8" vital area) on the gong to obtain acceptable accuracy for pronghorn. The full 12" would be acceptable on elk sized game or larger.
The first round cold bore limitation also brings another factor into the mix, wind. I have different distances I am comfortable shooting depending on wind speed and direction. A shot into the wind is much easier than a straight crosswind. The only way to learn your limitations in different conditions is to shoot regularly in ALL weather conditions and treat every shot as a learning experience.
I hope this is helpful and if I have missed something or if my methods are flawed feel free to set me straight.