If you go with a trusted builder then you can be confident you will get a quality frame that fits well. This quality and fit will cost you extra for sure. A friend of mine recommended Seven Cycles to me so I went with them. They gather various body measurements as well as information about your current bike. Then they call you and ask you what you like about your current bike, what you'd like to change and what type of riding you plan to do with your new bike. With all of that information they're able to build a frame that is optimized for you.
I have owned about a dozen bikes in my lifetime and my Seven fits me the best of any bike I've ever ridden. The seat tube on my Seven, for example, is 56.5cm (center to top) and the top tube is longer than you find on 56cm frames to account for my longer arms. In the past I've usually found 58cm frames to fit the best because of the need for a longer top tube. There are also several other factors that affect fit (seat post, saddle position, stem angle and length, bars, etc.) so the frame is just one part of the whole equation. A good bike shop should be able to get a reasonable fit out of most any frame provided they start with the right size.
One of the biggest drawbacks of going custom is you don't get to ride the bike before you buy it. I think this is the main gist of your question. For that you just gotta have faith, which is why going with a proven builder is a good idea. While custom frames aren't for everyone I couldn't be happier with mine.