Colorectal cancer arises as a consequence of the accumulation of genetic alterations (gene mutations, gene amplification, and so on) and epigenetic alterations (aberrant DNA methylation, chromatin modifications, and so on) that transform colonic epithelial cells into colon adenocarcinoma cells. The loss of genomic stability and resulting gene alterations are key molecular pathogenic steps that occur early in tumorigenesis; they permit the acquisition of a sufficient number of alterations in tumor suppressor genes and oncogenes that transform cells and promote tumor progression. Two predominant forms of genomic instability that have been identified in colon cancer are microsatellite instability and chromosome instability. Substantial progress has been made to identify causes of chromosomal instability in colorectal cells and to determine the effects of the different forms of genomic instability on the biological and clinical behavior of colon tumors. In addition to genomic instability, epigenetic instability results in the aberrant methylation of tumor suppressor genes. Determining the causes and roles of genomic and epigenomic instability in colon tumor formation has the potential to yield more effective prevention strategies and therapeutics for patients with colorectal cancer.