Games with Hex Grids that use Manhattan Distance will have trouble on Roll20. This one can't be fixed with the API, so far as I know. There's also no "Align to Hex Grid". GURPS has some issues due to the above, but also due to not being able to conveniently sum 3d6 before comparing it to a target number, and problems with critical value coloring. This can be overcome with the APIs. Dice pool games are by no means impossible, but certainly inconvenient; you can't have a character sheet listing all your dice pool values, and do a convenient equivalent to "/roll dexterity + ribbon-gymnastics" for all those oddball situational rolls that come up as a combination of creativity and good roleplay; and trying to macro them all out just becomes a combinatorical nightmare. This may be overcome with the APIs. While Earthdawn's exploding dice work, its step system isn't in by default. There are APIs for it, and you might be able to macro it in, but it's by no means doable in an elementary fashion. Exalted and various White Wolf games don't work by default either; you either need correctly done rollable tables or API use to get them to work correctly.