Tubulin protein is one of several members of a small family of globular proteins. It offers a potential target for anticancer drug design and development. Combretastatin A-4 (CA-4) is a potent anticancer and antiangiogenesis natural substance isolated from Combretum caffrum. Modifications on the CA-4 structure have led to a great number of novel CA-4 derivatives as potent tubulin inhibitors and high cytotoxic anticancer agents is becoming an interesting field, leading to a breakthrough in the treatment of cancer. In this review, the recent developments of novel CA-4 derivatives via the modifications on the A- and B-ring and the double bond as anticancer agents are discussed.