Understanding of the metabolism and mechanisms of resistance of tumors to chemotherapeutic agents is essential so that we can administer therapy to maximize response and minimize toxicity. In this review we describe molecular markers associated with fluoropyrimidine and platinum-based chemotherapy that may predict the outcome of therapy when patients are treated with these agents. We discuss the ways in which determination of gene expression levels can enhance the treatment of colorectal cancer through prediction of patient response and tailoring of chemotherapy to the characteristics of an individual tumor.