There is definitely a continuum. We spent years using Roll20 for a very heavily modified 2e/homebrew system. Roll20 worked just fine. We didn't use a lot of published modules, but those that we did use were absolutely fine and usable. As others said, the biggest challenges are the maps, dynamic lighting, tokens, handouts, and other images, and those are all universal. When we did switch to 5e, it was noticeably better because we could use the included character sheets (instead of keeping them on Dropbox and rolling everything manually, which is what we'd done before). For our new campaign (Zeitgeist AP), I invested a significant amount of time figuring out better ways to use Roll20, including the API functions and extensive use of token actions. These "push a button to resolve stuff" things are not at all necessary, but they speed gameplay tremendously and make the DM's life easier. They are simple for the players, but (at least for this non-programmer) required a significant amount of time (and $10/month) to figure out how to make all these cool bells and whistles work. Completely worth it, IMHO, but annoying that I had to learn from random forum posts and youtube videos and not through something easier and more integrated .
So, I'd say that the Zeitgeist adventures on Roll20 will work perfectly well regardless of which system (including homebrew) you decide to use, and are a great bargain even if you homebrew and don't value your own time very highly. If you are busy, they are a godsend, either to save you time or so that you can spend the same amount of time on the details and prep that make the sessions great as opposed to spending all your time on maps and tokens. If you actually use 5e, there are additional cool and helpful features that make things easier and faster (such as having rollable character sheets for all the NPCs & villains). I also highly recommend the Roll20 API if you are serious about your game. It's a lot of pain for a short time up front, but makes life so much easier on the other side. Some of the functions are 5e or Pathfinder-specific, but most will enhance any game. Token actions don't require API, and also help speed up the game (after some initial set-up pain).