I've certainly come across problems with both applications and games when using Vista x64. Most applications that do have a problem state quite clearly they aren't meant for 64-bit, but really the programs that do so usually have a separate 64-bit version. There are some that don't fit that pattern, but apparently none were notable enough for me to recall.
I have come across two specific game issues, however, as I test a fairly large amount of titles on Vista.
1) ArMA/Armed Assault - appears to have a bug with ATI drivers + Vista x64
Note: I believe this is a known issue and may be fixed, but meanwhile it might be fixable by using either an older driver or the default driver (may also be possible to mod a driver)
2) Brothers in Arms: Earned in Blood - cannot install because of Starforce copy protection
Note: This is a known issue and it seems unlikely it will be fixed officially (at least for this specific case)