Pharmacogenomic tools are beginning to emerge that will provide guidance in the treatment and prevention of colorectal cancer. Significant individual genetic variation exists in drug metabolism of 5FU, capecitabine, irinotecan, and oxaliplatin that influences both the toxicity and efficacy of these agents. Recent FDA approval of genetic testing for mutations in the UGT1A1 gene that predict adverse reactions to irinotecan is ushering in a new era that will increasingly rely on genotyping to individualize treatment decisions for patients with cancer as well as for patients at high risk who may be candidates for chemoprevention agents. This review focuses on current knowledge regarding key mutations and polymorphisms which affect outcomes for colorectal cancer patients, as well as the pharmacogenetics of chemoprevention trials.