As I dip my big toe into the water of amateur game design with a game I'm calling "Ice Age", I think my sweet spot is 4 players. Some games that allow for more either take way too long to play or, in an attempt to avoid long playtimes, are oversimplified. I have played several games recently that worked well with more than 4 players, including Resistance, Samurai Sword, and King of Tokyo. But for the game experience I am trying to create, my goal is to optimize for 4 players.
Even with 4 player in mind for the final product, I am finding that I'm building my gameplay and mechanics for 2. My reasons for doing so are entirely practical--more players means making more cards and finding more people to help test. Even so, I've got to keep in mind whether the game will become too clunky or cumbersome when I eventually scale up to the 4-player version.