This review looks back at five decades of research into genetic susceptibility to colorectal cancer (CRC) and the insights these studies have provided. Initial evidence of a genetic basis of CRC stems from epidemiological studies in the 1950s and is further provided by the existence of multiple dominant predisposition syndromes. Genetic linkage and positional cloning studies identified the first high-penetrance genes for CRC in the 1980s and 1990s. More recent genome-wide association studies have identified common low-penetrance susceptibility loci and provide support for a polygenic model of disease susceptibility. These observations suggest a high proportion of CRC may arise in a group of susceptible individuals as a consequence of the combined effects of common low-penetrance risk alleles and rare variants conferring moderate CRC risks. Despite these advances, however, currently identified loci explain only a small fraction of the estimated heritability to CRC. It is hoped that a new generation of sequencing projects will help explain this missing heritability.