Best practices and strategies for combatting malware

What are the best strategies and tactics to take care of the onslaught of malware/Trojan horses in a network?

I am handling an enterprise 24/7 network with an antivirus solution in place along with security like a firewall. But, I am worried on how to protect my network from malware such as P2P worms and Trojan horses especially since a lot of users have access to Internet.