Most lesions of the colon, rectum, and anus can be biopsied only by using an endoscopic device. Adequate patient and bowel preparation, close communication with the pathologist, and meticulous handling and documentation of the specimen are required to ensure an accurate histologic diagnosis. Although somewhat controversial, most investigators agree that all but the smallest neoplasms of the colon and rectum should be excisionally biopsied when possible, incisionally biopsied when excision is not feasible, and destroyed if they are multiple, small, and not suspected of malignancy. Future studies will focus on the cellular biologic characteristics of the biopsy specimen to define more accurately the appropriate treatment plan and prognosis for patients.