With effective chemotherapy as adjuvant treatment, the survival benefit is clearly achieved for certain (stage III) colorectal cancer patients, though there still exist many unsettled issues including the controversies in the treatment of stage II disease. Advances in the development of a new generation of cytotoxic agents in the past several years have allowed us to move forward from the "fluorouracil-only era" in the treatment of advanced/metastatic colorectal cancer. It is still not very clear how best to minimize toxicity without compromising efficacy of the combination therapy with newer agents, or how to maximize the benefit of chemotherapy (concurrent versus sequential). There are many current ongoing clinical trials designed to address these issues. With better understanding of the signal transduction and molecular biology characteristics of colorectal cancer, and the development of biologic and molecular target agents, the outcomes of patients with colorectal cancer will be improved further. Future clinical trials should be focused on optimizing and individualizing therapy for patients based on their molecular profiles to achieve maximal clinical benefit.