The treatment of patients with metastatic colon cancer has evolved tremendously over the past 10 years, with improved overall survival (OS) rates as a result of the advent of several important agents. Following the results of important adjuvant trials, the incorporation of oxaliplatin into the adjuvant setting has significantly increased the disease-free survival and OS rates in patients who undergo curative resection. However, still a significant number of patients will present with recurrent disease after being treated with oxaliplatin-containing chemotherapy regimens. Herein, we present approaches to the chemotherapeutic management of such patients with a review of the literature.