Several developments in the past few years have incrementally progressed the field and provided additional insights into the management of advanced colorectal cancer. This review discusses the components of current cytotoxic chemotherapy regimens for advanced colorectal cancer: fluorouracil (5-FU), capecitabine (Xeloda), irinotecan (Camptosar), and oxaliplatin (Eloxatin). The equivalence of several front-line regimens has provided opportunities for increased tailoring of therapies for individual patients. Preliminary data on pharmacogenomics provides hope that we will be able to better match patients with regimens and doses on the basis of individualized predictions of toxicity and response. The importance of second-line therapy in overall survival has again been highlighted; the best outcomes have occurred in patients treated with 5-FU, oxaliplatin, and irinotecan in combination with targeted therapies during the course of their disease. Elderly patients are no exception to this finding. Combination regimens and second-line therapy should be offered to elderly patients who have adequate performance status and no contraindicated comorbid conditions, without regard for their chronological age.