Surgery remains the only curative therapy for colon cancer. However, several studies during the last years have proved that systemic chemotherapy in the adjuvant setting definitely improves the curative rate for those patients with localized colon cancer. The combination of 5-fluorouracil (5-FU) and leukovorin (LV) remained the reference treatment for over a decade. However, oxaliplatin-based chemotherapy has emerged as the new standard of care in adjuvant treatment of stage III colon cancer. The role of adjuvant therapy in stage II cancers remains controversial and its routine use is recommended only in high risk patients. This review focuses on the efficacy, safety and toxicity of several drugs used in the adjuvant treatment of colon cancer and on clinical issues, such as the timing for initiation of chemotherapy, its duration and treatment of special patient subgroups, such as stage II or elderly patients.