So many settings, both mythology and science fiction ones that go completely underused because RPG developers tend to focus on standard fantasy fare.
I am so sick that imagination always has to be lowered to the most common audience member instead of making them have to increase their knowledge in order to fully understand the settings.
Greek Mythology, Roman Mythology, Egyptian Mythology, the Mythologies from Indian, China, Korea, Japan, and so many others that are in general ignored. Only the occasional rare game here in the West and probably local games developed in Asia that will never come over here because of the language barrier and the culture differences.