For the last 40 years, 5-fluorouracil (5-FU) has remained the treatment of choice in both the adjuvant and advanced treatment of colorectal cancer (CRC). However, 5-FU monotherapy produces response rates of only 10-20% in the advanced setting. 5-FU has been combined with newer agents, such as oxaliplatin and irinotecan, and this has significantly increased response rates to 40-50% in the advanced setting. More recently, novel biological agents, such as the monoclonal antibodies targeting either the epidermal growth factor receptor or vascular endothelial growth factor, have shown to provide additional clinical benefit for patients with metastatic CRC. A number of predictive markers have been identified for CRC to date. However, their usefulness as individual markers of response has led to somewhat inconclusive results. Therefore, there is a need to identify panels of predictive markers of response to therapy for advanced CRC, in order to improve these disappointing response rates. The advent of high-throughput methodologies, such as microarrays, enables tumor samples to be profiled on a global scale. This technology has been utilized to develop predictive markers for a wide range of tumor types to date, and hopefully this technology can be translated into the CRC setting with the hope of predicting the response of each individual tumor to chemotherapy.