Oxaliplatin is a new third-generation platinum analogue with unique activity in colorectal cancer. This agent has changed the approach to chemotherapy for this disease. Novel biologic or molecular targeting agents are now under study in phase I to III clinical trials. Many of these agents are quite promising in colorectal cancer therapy. Most advanced among these include anti-vascular endothelial growth factor antibodies, antibodies directed against the epidermal growth factor receptor (HER-1), small-molecule tyrosine kinase inhibitors of epidermal growth factor receptor, and the proteasome inhibitor PS-341 (bortezomib). The rationale for combinations with oxaliplatin and early clinical trial results are discussed.