Colorectal cancer (CRC) is a leading cause of cancer death and archetype for cancer as a genetic disease. However, the mechanisms for genetic change and their interactions with environmental risk factors have been difficult to unravel. New hypotheses, models, and methods are being used to investigate a complex web of risk factors that includes the intestinal microbiome. Recent research has clarified how the microbiome can generate genomic change in CRC. Several phenotypes among a small group of selected commensals have helped us better understand how mutations and chromosomal instability (CIN) are induced in CRC (e.g., toxin production, metabolite formation, radical generation, and immune modulation leading to a bystander effect). This review discusses recent hypotheses, models, and mechanisms by which the intestinal microbiome contributes to the initiation and progression of sporadic and colitis-associated forms of CRC. Overall, it appears the microbiome can initiate and/or promote CRC at all stages of tumorigenesis by acting as an inducer of DNA damage and CIN, regulating cell growth and death, generating epigenetic changes, and modulating host immune responses. Understanding how the microbiome interacts with other risk factors to define colorectal carcinogenesis will ultimately lead to more accurate risk prediction. A deeper understanding of CRC etiology will also help identify new targets for prevention and treatment and help accelerate the decline in mortality for this common cancer.