We recently upgraded a large Django app from 1.4 to 1.6, we actually begun the transition when Django was on 1.6b1 as we hoped they would hit stable before we were ready for production (they did). To be honest the only issues we had were 3rd party apps that had not been updated, which wasn't surprising as 1.6 was still in Beta when we began. And as 1.6 neared release we found fewer and fewer apps that still had problems.

Beyond that it was pretty straight forward, but it really helps if you have good unittests to begin with.