Environment or genetic constitutions can lead to an increase of genetic or epigenetic events and increase the risk for malignancy. Genomic instability is seen in most types of malignancies. Two forms of genetic instability have been described in colorectal cancer: chromosomal instability (CIN), and microsatellite instability (MIN). Almost all sporadic MIN tumors occur in the proximal colon, whereas most sporadic CIN tumors are distributed in the distal colon. The two familial syndromes, familial adenomatous polyposis and Lynch syndrome, constitute models for the different carcinogenic mechanisms in CIN and MIN tumors, respectively. This article reviews the principal differences between CIN and MIN tumors, evidence for a proximal and distal route in carcinogenesis, gender differences, and aspects of methylation in CIN and MIN colorectal tumorigenesis.