Systemic therapy for metastatic colorectal cancer is evolving rapidly after many years without significant change. Standard adjuvant therapy for rectal cancer, on the other hand, remains much the same as it has been since the early 1990s. Recent additions to the colorectal cancer armamentarium include capecitabine, irinotecan, and oxaliplatin. Use of these agents in metastatic colorectal cancer and potential for use in localized rectal cancer are discussed. In addition to these "classical" chemotherapeutic agents, there are a number of exciting therapies designed to target specific molecular features of malignant cells. These agents are now being tested in colorectal cancer in addition to chemotherapy and to radiotherapy, with the hope that improvements in outcome will be made without substantial increases in treatment toxicity. The focus of the section on newer classes of agents will be on agents that are in phase II and III trials, with brief mention of other exciting treatment strategies.