Colorectal cancer is the second most common cause of cancer death in the United States. Understanding the biochemical pathways underlying carcinogenesis has paved the way for more effective treatments and better outcomes. BRAF mutation testing has a role in (1) differentiating sporadic colorectal cancer from Lynch syndrome, (2) identifying cancers lacking BRAF mutation that are more likely to respond to epidermal growth factor receptor inhibitor therapy, and (3) conferring worse prognosis in colorectal cancer that is microsatellite stable. Several analytic methods are available to reliably detect BRAF mutations. Real-time polymerase chain reaction identifies the most common BRAF mutation, V600E, in frozen or paraffin-embedded colorectal cancer tissue. Traditional DNA sequencing and the somewhat more-sensitive pyrosequencing method can detect multiple alternative BRAF mutations that are predicted to constitutively activate signaling through the MAPK pathway, promoting tumor growth and survival. Pathologists play an important role in assay validation as well as in consulting with clinicians about indications for testing, ensuring quality of testing, and interpreting results in conjunction with other clinicopathologic factors important in the management of affected patients.