What do you know how to hack? If you are familiar with something like the SNES then in many cases the megadrive/genesis is easier to hack, give or take the lesser state of the debugging emulators (I am not sure what we are suggesting right now for this). http://www.romhacking.net/documents/277/
covers hardware things pretty nicely.
There is no file system to pull apart and it is all in the ROM like most systems of the day and older, no set formats for things and space is likely to be an issue, though you do mostly dodge bankswitching and weird memory mapping which is nice. By similar token most tile editors if they are not highly specific (most aren't) will have a megadrive/genesis mode.
If you are not familiar with hacking then I am probably supposed to point you at http://www.romhacking.net/start/
Also what do you want to hack? Text, stats, high level logic in the game, graphics, music and levels probably all have rather different approaches. We can cover whatever you like but there is no point in spending 3 hours covering text editing if you want to edit some stats or make some cheats or something instead.