This is a tough question since there isn't really a number one thing to think of in game development. Because a game must maintain interactive framerates (at least for real-time graphics games) there are about a hundred number one things to think of when developing a game engine. Overall I personally feel that speed and memory management are probably two of the biggest issues to think about.
What is the number one thing to think of when developing a game engine that fits the above criteria? For example, speed of operation? Solid memory management? etc. etc..