Adjuvant therapy of colorectal cancer is one of the most active areas of clinical oncology research. Although the data for the benefits from early trials of adjuvant therapy were inconclusive, these trials suffered from inadequate sample sizes, poor staging, potentially suboptimal treatment regimens and ill-defined prognostic subgroups. More recently, larger trials of higher scientific quality have demonstrated that regimens of fluorouracil plus levamisole in stage III colon cancer and fluorouracil with postoperative radiation in stages II and III rectal cancer can reduce mortality. Such regimens have now become standard practice in settings in which treatment is believed to be both efficacious and tolerable, and when the overall impact of therapy is considered to be clinically relevant. More recent advances in adjuvant treatment of colorectal cancer further support the role of fluorouracil-based regimens. Peri-operative portal vein infusions of fluorouracil demonstrate improved relapse-free and overall survival, and infusional fluorouracil administered with radiation for rectal primaries appears superior to less intensive bolus fluorouracil regimens. Completed trials of fluorouracil plus leucovorin combinations are awaiting maturation, with expectations for superior adjuvant activity based on demonstrated improved response rates for biochemically modulated fluorouracil in advanced metastatic colorectal cancer. New systemic agents are also entering large-scale adjuvant trials, including monoclonal antibody 17-1a, given alone and in conjunction with standard fluorouracil regimens. Additional cytotoxic drugs, including CPT-11 and Tomudex, offer new opportunities for alternative adjuvant regimens for the large, heterogeneous population of patients with resected colorectal cancer.