The importance of primary tumor sidedness and its effect on prognosis in patients with metastatic colorectal cancer (mCRC) has recently been spotlighted. The observation that the site in the colon where a tumor originates is relevant to outcomes dates back to 2001. O’Dwyer et al1 reported a nearly 5-month difference in median overall survival (OS) (15.8 vs 10.9 months, P < .001) for patients with mCRC who had left-sided vs those with right-sided primary tumors in the phase 3 trial E2290. In that era, fluorouracil was the sole treatment, and median OS hovered around 1 year. Given the advances in cytotoxic chemotherapy and biologic drug development in the last 15 years, the plethora of clinical trial data available for analysis, and the advances that have been made in molecular genetic subtyping, the topic is worth revisiting.