The prognosis of colon cancer is primarily determined through staging of the disease. After curative surgery, clinically occult micrometastases are thought to be the major source of disease recurrence. The main aim of postoperative systemic treatment is to eradicate micrometastases, thereby improving outcomes with an increased cure rate. Adjuvant systemic chemotherapy is indicated for patients with stage III colon cancer, as well as for patients with high-risk stage II colon cancer. Prognostic and predictive markers that identify heterogeneous groups are needed to implement tailored therapeutic strategies. Due to the lack of evidence of predictive value of multigene assays in terms of potential value of adjuvant chemotherapy, multigene assays should not be used to determine adjuvant therapy. The standard treatment for most patients with stage III disease is a combination of oxaliplatin with infusional and bolus 5-fluorouracil (5-FU) or with an oral agent such as capecitabine, which has equivalent results. Adjuvant therapy should not be administered to all patients with stage II colon cancer. High-risk stage II patients may be considered as an eligible group for adjuvant therapy after a complete discussion. There is no high level of evidence to use irinotecan-based combination chemotherapies in the adjuvant setting. The antiangiogenic agent bevacizumab in combination with standard adjuvant chemotherapy regimens also failed to improve outcomes, as did the EGFR agent cetuximab.