It comes down to a handful of things. A good pair of cycling shorts, chamois cream, a saddle that FITS your butt, good fit on the bike, and so on.
Since it sounds like you do a fair amount of cycling, I'm assuming that you already have several good pairs of cycling shorts (with a chamois). Sometimes you have to experiment with different manufacturers. Don't be cheap when it comes to your comfort on the bike. Spend the money on a good pair of shorts that have a nice, thick chamois. Preferably get a synthetic chamois versus natural - this is for hygenic reasons.
You should also be using a good chamois cream. That will save your butt on long rides and prevent chafing.
Saddles are like shorts. Sometimes you have to keep trying saddles until you find one that works for you. Some shops (though rare) will even have demo saddles that you can try out. At the very least, try hopping on some bikes in the store to tryout the saddles on the new floor bikes.
Position will also help. You want your weight to be evenly distributed on the bike, so that no one part is carrying the bulk of your weight. Go to a reputable bike shop to see about getting a proper fit done. This should be done on your bike, on a stationary trainer with you in your riding gear.
I'm sure there are more factors to consider, but these are the major ones off the top of my head.