In patients with IBD, chronic colonic inflammation increases the risk of colorectal cancer, perhaps because inflammation predisposes these tissues to genomic instability. Carcinogenesis in the inflamed colon seems to follow a different sequence of genetic alterations than that observed in sporadic cancers in the uninflamed colon. In this Review, we focus on the genetic alterations in colitis-associated colorectal cancer that contribute to the acquisition of the essential hallmarks of cancer, and on how those alterations differ from sporadic colorectal cancers. Our intent is to provide a conceptual basis for categorizing carcinogenetic molecular abnormalities in IBD, and for understanding how cancer-preventive therapies might target reversal of acquired abnormalities in specific biochemical pathways.