Like most D&D games that I play now, there are often gaps of months between sessions. This game in particular has been known to have up to seven month gaps between games, making it a challenge to present the game (which is entirely interconnected) in short enough of chunks to make it so each portion is memorable and does not take too much catching up when we start the next session.
Another major challenge is that we are using the D&D game system to play a Japanese role-playing game that had its own complex (and awesome) system for character advancement. Like most JRPGs, Dragon Warrior 7 relies on a lot of level grinding (battling over and over again to get experience), fetch quests, and blocking off areas with low (or even non-existent) barriers that would not block people in real life, let alone in a magical world. This has required a great deal of innovation on my part to stay true to the overall story and world of the video game while still allowing the characters the sense of freedom that pen and paper role-playing is known for.
Probably one of the most difficult challenges is dealing with the fact that three of the players are DMs themselves. So often, all it takes is a simple description of a creature and these players automatically know its strengths and weaknesses. I have to constantly work at keeping the game as fresh and interesting as possible, while still holding to the rules that they know (and know how to exploit).
In the case of today's adventure, that meant creating encounters with creatures that were rare (although one player recognized it right away), or completely made up while still based on more familiar creatures. It also meant streamlining a great deal of the NPC encounters so that the "fetch quest" aspect of the original material was minimized. I also had to account for the fact that my players' characters had access to magical transportation (specifically flight) that the video characters don't have.
We still had to spend an hour and a half catching up on the adventure before we could begin, but I believe that everyone had a good time. I did, which is not always true when I'm DMing as I prefer to play. But it was hearing that my friends had a good time that made it worth the effort.