The introduction of oxaliplatin into the colorectal cancer setting represents a significant advancement in the treatment of the disease. Synergistic effects with traditional therapy 5-fluorouracil/folinic acid have increased response rates significantly, improved time-sensitive response parameters, and facilitated the removal of previously unresectable hepatic metastases, thus changing the natural history of the disease. Ongoing and planned trials are identifying various issues that need to be addressed to fully realize the potential of oxaliplatin. These include optimization of dosing and schedule of administration, determination of the most effective oxaliplatin-5-fluorouracil/folinic acid combination, definition of the role of new thymidylate synthase inhibitors with respect to oxaliplatin therapy, and identification of the most effective combinations of oxaliplatin with the new anticancer agents that have been recently introduced. Providing the answers to these questions will contribute to changing the attitude of the clinical oncologist regarding what strategy to adopt in treating colorectal cancer in the coming years.