The relevance of genetics to colorectal disease lies mainly in its application to the origin, classification, and management of two groups of diseases: colorectal neoplasia and inflammatory bowel disease (IBD). While knowledge of genetics is helpful in both areas, the extent to which genetics contributes to an understanding of the disease processes differs. The two sets of diseases both involve perturbations of the regulatory pathways of two very important sets of bodily functions: for cancer, the functions are cell division (in particular, the fidelity of DNA replication), growth, differentiation, and death, and for IBD, they are mucosal immunity and interaction with the intestinal microbiome. This chapter discusses the role of genetics in tumorigenesis and inflammation in the intestinal tract, comparing cancer with inflammatory bowel disease.