For the past 40 years, the mainstay of chemotherapy against colorectal cancer has been 5-fluorouracil (5-FU), often administered in recent years with folinic acid modulation. Traditional platinum derivatives have generally been ineffective in colorectal cancer therapy; however, the third-generation 1,2-diaminocyclohexane-platinum derivative oxaliplatin has shown good antitumor activity and a lack of cross-reactivity with cisplatin. Oddly, oxaliplatin was first developed as a combination therapy with 5-FU plus folinic acid administered as a chronomodulated infusion over 5 days. In subsequent phase II clinical trials, the activity of single-agent oxaliplatin was assessed in 63 previously untreated patients and 139 patients with metastatic disease refractory to 5-FU. In first-line therapy, the median overall survival was approximately 13 to 14 months, whereas in previously treated patients no longer responding to 5-FU, it was 8 to 10 months. The 18% objective response rate obtained with first-line therapy confirms that the activity of single-agent oxaliplatin is comparable to other anticancer therapies considered active against colorectal cancer. The 10% response rate obtained in second-line therapy in patients refractory to 5-FU provides a means for palliative care and suggests the possibility for a potentially active combination regimen with 5-FU.