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Some homebrew may require manual DLDI patching to work.
In newer editions of the FW, it has an option to use the common files. It lacks compatibility with many new games and it has a problem displaying cheat codes if there are too many. Some older ROM trimmers cut off too much data from the ROM and break download play, along with causing other issues. As of firmware 1.10, the R4 unit patches automatically.
All future Anti-Piracy ROMs are not supported but could possibly be fixed on a 1:1 basis. You will need to rename your save files in order to make use of them. Including Wii-connectivity, Cheats, Themes, Short-cuts, etc. However, it has not been updated since April 24, 2008. However, NDSTokyo Trim is widely considered to be the best trimmer at this time.
I won't say it is 100% because there could be the occasional glitch or bug. Firmware 1.18 is the latest official firmware for the R4DS.
This has been fixed with PAlib 070206 for devkit ARM r20 however not all projects have been updated for these new releases.