This article reviews the various systemic therapy options for patients with metastatic colorectal cancer (CRC) that is judged to be noncurable. The choice of initial therapy depends on patient preferences, treatment goals, performance status, and presence of comorbid conditions. Whether surgical resection of the primary tumor should be considered in patients who present with metastatic CRC is a matter of controversy. The components of the initial systemic regimen influence the options for second- and third-line options when disease progression occurs during therapy. The standard of practice is often to continue chemotherapy until progression, unacceptable side effects, or death. In patients with incurable CRC, the balance between efficacy, toxicity, and repeated hospital or clinic visits must be discussed with the patient. Although continuous treatment may be appropriate for some patients, intermittent treatment strategies or maintenance with the least toxic agents may be preferable for others. If disease progression occurs during a chemotherapy break or while the patient is on maintenance therapy, previously used agents may be reintroduced provided that preexisting toxicities have resolved.