Background: The 12-gene colon cancer assay is the first commercially available molecular assay to predict the risk of recurrence in stage II/III colon and rectal cancer. Rigorous evidence for clinical validity and utility of an assay is imperative since the result is used for treatment decision-making. This summary outlines the studies that meet an established definition of clinical validation and additional studies that support the utility of the assay. Methods: Prospectively designed studies using archival tissue with pre-specified methods, clinical outcomes, and analysis plan were considered clinical validation studies (Simon et al. JNCI 2009). Additional studies that demonstrated the utility of the assay in a clinical setting were considered supportive. Results: The assay has been clinically validated in four independent studies with 3,315 patients (2,390 stage II/628 stage III colon and 130 stage II/167 stage III rectal). All four studies demonstrated a significant association (p<0.05) between the result and outcome (e.g. recurrence risk and cancer specific survival). The score was examined in the context of other variables, including T and N stage, mismatch repair status, number of nodes examined, lymphovascular invasion, and tumor grade; across all studies, the result consistently contributed to risk stratification beyond these variables. Three clinical utility studies with 502 patients showed that 29-45% of initial treatment recommendations in stage IIA colon cancer were changed, with a net reduction in use of adjuvant chemotherapy. Conclusions: Clinical validation of the 12-gene assay followed a now-standard approach of using archived tissue from multiple large, prospectively-designed studies with documented long-term outcomes; the 12-gene colon assay meets level IB evidence criteria. Subsequent studies showed the assay has impact on clinical practice. The underlying tumor biology assessed by the score is relevant in both colon (stage II and III) and rectal cancer, providing information beyond conventional features, and can help guide treatment decisions regarding adjuvant chemotherapy.