Irinotecan (CPT-11 [Camptosar]) is currently approved for use as a second-line agent in the treatment of metastatic colorectal cancer. Phase II studies have also shown substantial single-agent activity of irinotecan in the first-line treatment of metastatic colorectal cancer. Response rates appear to be similar to those seen with standard first-line regimens, although direct randomized comparisons have not yet been reported. In the absence of definitive data showing irinotecan to be superior, its routine use as a single agent in the first-line treatment of colorectal cancer may be hard to justify, given the significant cost differential between irinotecan and current standard first-line regimens. Studies exploring combinations of irinotecan with fluorouracil may identify a first-line role for these combination regimens. Also, use of specific molecular markers may permit the identification of selected patients with tumor characteristics that would specifically favor consideration of upfront irinotecan monotherapy.