Qt? Tk? I've used both cross-platform and both work great for desktop operating systems (and unlike in the olden days, Tk's themed widgets actually look reasonably native now). Qt's only downside is the licensing and the sheer size of it, and Tk's only downside (for my use cases) is the lack of an embeddable browser widget; in both cases these are issues regardless of platform.
The actual cross-platform issues, from what I've seen, are more to do with the non-GUI pieces. For example, Windows and macOS/Linux printing are wildly different from one another, and all three operating systems have wildly different strategies for packaging and distributing applications (especially when writing the program in a scripting language like Python or Ruby or what have you instead of something precompiled like C++ or Rust; with Linux this is trivial, and with macOS this is less trivial but manageable, but with Windows this is a royal pain in the ass).
On another note, I'm currently looking into Avalonia and .NET Core as another potential option in this space; from preliminary testing, .NET Core looks like it mostly addresses the issues I've encountered (it certainly makes it easy to cross-compile for Windows/Mac/Linux, and I'm hoping it'll eventually subsume Xamarin or portions thereof to enable easy Android and iOS builds, too), so whether or not this becomes my go-to hinges on whether or not Avalonia itself is ready for primetime (and while simple examples seem to be promising, as are more complex examples like the Avalonia version of ILSpy, I'm still actively investigating).
