The current phase III studies of chemotherapy in advanced colorectal cancer include 60% to 85% of patients with the liver as a site of metastatic disease. Within the past 10 years, various modulatory combinations of 5-fluorouracil (5-FU) with agents such as leucovorin, interferon, N-(phosphonacetyl)-L-aspartate (PALA), and methotrexate have produced higher response rates than 5-FU alone. A major seven-arm study, conducted by the Southwestern Oncology Group and reported in 1995, suggested that single-agent, continuous-infusion 5-FU demonstrated the most encouraging results. Nine of 12 reported randomized studies comparing the combination of 5-FU and leucovorin with 5-FU alone report significant increases in response rates; two studies reported significant increases in survival. The meta-analysis project involving 1381 patients confirmed the increase in response rate with the combination (23%) vs. 5-FU alone (11%) but did not demonstrate any significant difference in median survival. The current issues involving 5-FU administration largely concentrate on the best approach (modulation vs. scheduling) and comprehensive evaluation of end points (quality of life, survival, and pharmacoeconomics). The current literature examining quality-of-life issues suggests that 5-FU and low-dose leucovorin produce the best overall improvement in symptoms. Others argue that continuous-infusion scheduling is also associated with a very good quality of life (although the increased cost and morbidity of continuous-infusion administration has to be factored into this consideration). An important phase III study is currently being conducted by the National Cancer Institute of Canada comparing immediate vs. delayed (until symptomatic) chemotherapy in patients with advanced colorectal cancer. Of the new approaches to therapy, perhaps the most immediately applicable are the new thymidylate synthase inhibitors (in particular, Tomudex, which produces a response rate equivalent to that of 5-FU plus leucovorin with less toxicity and a more convenient schedule).