Colorectal cancer was one of the first solid tumors to be classified on the basis of molecular profiling. Microsatellite instability has allowed researchers to distinguish a specific subtype of colorectal cancer that has a clearly identified molecular origin (mismatch repair deficiency), arises on a hereditary and sporadic basis, is linked to a clear clinicopathologic profile, and has prognostic implications. Inconclusive predictive data along with a paucity of targeted drug development have prevented this molecular classification system from being implemented in the clinical setting. New high-throughput genomic data have validated it, thus stressing the fact that it is ready to be applied clinically. Significance: Application of a molecular classification of colorectal cancer in the clinical arena is an unmet promise. Recent results of large-scale genomic analyses have provided confirmation and further insights into the molecular biology of already known colorectal cancer subgroups. The quintessential example is the microsatellite instability subgroup, which has been well characterized during the past 2 decades. Future drug development and clinical research initiatives in colorectal oncology should consider these and other known cancer subgroups and start targeting these selected patient populations. © 2013 American Association for Cancer Research.