An estimated 150,000 individuals are diagnosed with colorectal carcinoma (CRC) each year, and approximately 50,000 will die from this disease, making CRC the third leading cause of cancer deaths in the United States. For this reason, an enormous amount of effort has been spent to understand the molecular pathogenesis of this disease and to develop screening tests and prognostic markers. In the last 10 years, there has been a revolution in the understanding of CRC due to the identification of multiple distinct molecular pathways. With the introduction of biologic agents that target particular subtypes of CRC, molecular analysis of CRC is becoming standard of care in surgical pathology. In this context, the authors first describe the multiple molecular pathways leading to CRC and then discuss the role of molecular testing in the diagnosis of Lynch syndrome (formerly hereditary nonpolyposis colorectal carcinoma), prognosis, and therapy.