Wine has some outstanding usability issues. This page serves as a way to catalog what they are, who is working on them, and how we can fix them.
A lot of users attempt to run various programs in Wine before having OpenGL fully configured on their system, generally as a result of lacking proprietary NVidia drivers. It would be nice if Wine warned the user that DirectRendering was not working when running an OpenGL application, along with a suggestion to install drivers.
This is partially fixed, as Wine will output a console command, but it would be nice to consider something graphical.
Currently Wine creates menu entries akin to the Windows start menu, however a few important items are lacking that most users aren't even aware exist until being told otherwise. Among these are winecfg, wine's uninstaller, and a link to browse Wine's virtual windows drive (ie, open up a ~/.wine/drive_c/ window in the file manager).
This can be fixed at the package level. The Ubuntu packages for instance include a few .desktop files to make this easier.
It has been suggested that winecfg's application tab be refactored in such a way to make it more intuitive. It is not always clear to new users that the selected application is linked to other tabs and not just for setting the Windows version (despite the descriptive text above the list box, and the title bar changing). See Bug 6233 and Bug 12441.