Oxaliplatin, a platinum compound characterized by a diaminocyclohexane (DACH) platinum carrier ligand, has proven its efficacy in first- and second-line advanced colorectal cancer (CRC) treatment. Acute reversible and cumulative peripheral sensory neuropathy has been observed frequently with oxaliplatin treatment and limits its use. Its synergism with other drugs, as well as its different mechanism of action and toxicity profile make it an attractive candidate for combination studies in CRC. It can be combined safely with 5-fluorouracil (5-FU)+/-folinic acid (LV), irinotecan, raltitrexed, multitarget antifolate LY231514 (MTA), and oral 5-FU prodrugs. These combinations confer both an increased response rate compared to that of any single agent and an increased secondary surgical resection of initially unresectable metastases, possibly leading to prolonged survival. In three prospective randomized phase III studies in advanced CRC, oxaliplatin plus 5-FU/LV improved significantly progression-free survival without a significant increase in median survival time and without affecting quality of life, compared to treatment with 5-FU/LV. Ongoing clinical trials will define its role in the adjuvant setting.