The Cancer and Leukemia Group B Gastrointestinal Cancer Committee was organized in the late 1970s under the leadership of Michael Perry and Philip Schein and began full-scale operations in the mid-1980s. Today, it is a multidisciplinary team of surgeons, radiation and medical oncologists, statisticians, quality-of-life experts, pharmacogeneticists, basic scientists, and community oncologists who design studies that are conducted across the United States. The Committee has done trials in patients with esophageal, gastric, pancreatic, colon, rectal, and anal cancers. New initiatives are under way in hepatocellular cancer, cholangiocarcinoma, and neuroendocrine tumors originating in the gastrointestinal tract. The Committee has increasingly concentrated on translational studies using tumor blocks, germ-line DNA, and plasma to evaluate biological correlates of tumor response and clinical outcomes. A broad program of pharmacogenomics has been incorporated for virtually all studies, including trials that prospectively use polymorphisms in drug-metabolizing genes to assign treatments. Future efforts aim to evolve new standards of care, evaluate new therapies, and answer relevant biological questions in gastrointestinal cancer.