Joe Harris published an excellent post detailing how you can use Flexible Packet Matching to recognize (and potentially block) Skype traffic. The solution depends on recognizing the first four bytes sent by the Skype application in a TCP session. While this is a great idea, you have to be aware that there's always a non-zero chance of false positives, more so as the described filter is testing the beginning of the payload in every TCP packet (not just the first data packet in the session).
Ivan Pepelnjak, CCIE#1354, is the chief technology advisor for NIL Data Communications. He has been designing and implementing large-scale data communications networks as well as teaching and writing books about advanced technologies since 1990. See his full profile, contact him or follow @ioshints on Twitter.