Sometimes. Some programs are too demanding (e.g. it might be completely ridiculous like Quake 3 or an N64 emulator, be too reliant on floating point code, etc.), or have requirements for things that aren't present on the '2x like the X Windowing System, or controls that won't be very compatible. The things that port most cleanly are SDL applications.
Don't put a million question marks in your title, be more descriptive. It's exceedingly annoying to see threads with names like this.