While most games from this collection get by with a 3-button Mega Drive controller (A, B, C buttons), others support the usage of 6-button Mega Drive controllers (with the extra buttons X, Y, Z). Of course all the above mentioned tools can be used for any game that natively lacks joystick/joypad support, not only for this emulator. I've been using Joy2Key for free ever since and was able to bind all keyboard keys to my xbox360 controller, even the quick save/load keys (F5/F9) and the 'quit to menu' key ESC, which allows me to navigate through the Sega emulator without having to use the keyboard at all. There are several programs that emulate keyboard and mouse input with a gamepad such as JoyToKey, Xpadder, Pinnacle Game Profiler and Enjoy2. If your controller is not recognized, a turnaround to make it work for this emulator is to use a tool that will bind your keyboard's keys to your controller. I didn't have any issues with generic controllers that look like PS2 controllers, while my wireless xbox360 controllers would not be recognized.

Some USB controllers are supported by this emulator, others are not. You can change the button to key mapping for both players in the emulator by going to 'Options/Input Configuration' or switch from the keyboard to controller(s).

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