Resistance to chemotherapy limits the effectiveness of current cancer therapies, including those used to treat colorectal cancer, which is the second most common cause of cancer death in Europe and the United States. 5-Fluorouracil-based chemotherapy regimens are the standard treatment for colorectal cancer in both the adjuvant and advanced disease settings. Drug resistance is thought to cause treatment failure in over 90% of patients with metastatic cancer, while drug resistant micrometastic tumour cells may also reduce the impact of adjuvant chemotherapy treatment. The identification of panels of biomarkers that not only identify those patients most likely to benefit from chemotherapy treatment, but also which chemotherapies to use, would be a major advance. In this review, we describe molecular mechanisms of drug resistance that may be relevant to colorectal cancer. We also describe the results of predictive biomarker studies in this disease. Finally, we discuss how pharmacogenomics and other high through-put technologies may impact on the clinical management of colorectal cancer in the future.