Good to see that everyone pretty much agrees that the answer to this question is very much a personal one. While most calibers have their limitations they can pretty much be broken down into catagories as James stated, with limitations attached. The factors in play, at the time of the shot, influence the decision to attempt or not, wind, light, angle, breathing, adrenalin, etc. Proficency comes with practice, limitations come with one being honest with him/her self. Everyone makes this decision once their finger makes contact with the trigger. For most of my hunting (other than DG) I have used my .338 Win Mag for the last 25 yrs. With 180gr Accubonds @ 3100fps and it is extremely accrurate. While I would prefer shots under 200 yds, I practice out to 500yds and would not hesitate to take this kind of shot if there was no other way to get closer and the rest of the conditions were "right". The caliber & bullet are more than adaquate at that range. Hunting in the mountains in the East Cape I made quite a few "across canyon or down into the canyon" shots between 348 yads up to 521yds. All one shot kills, from as small as a Bushbuck to as large as a Cape Eland (The Eland was shot with 210gr Nosler Partition at 348yds with complete penetration). Shooting accurately is 99% mental. Practice and know your rifle and ballistics. Before you squeeze off that shot, have the confidence to KNOW exactly where the bullet will strike. If you can do that, these kind of shots are not only "doable", they are ethical.