Human cancers are believed to develop in multiple stages. There is morphologic evidence for this in many tissues, including cancers of the lung, esophagus, head and neck, skin, colon, cervix, and bladder; and corresponding genetic models are developing. This article summarizes reports describing the timing and frequency of p53 alterations (i.e., mutation and/or protein accumulation) in progenitor lesions of human lung, esophagus (both squamous and Barrett's), head and neck, and colon. In squamous lesions of the lung, esophagus, and head and neck, there is evidence for p53 alteration in a minority of the earliest dysplasias and in a majority of the late or severe dysplasias. It is not known whether all of the alterations are caused by mutations or by epigenetic factors. In sporadic colonic adenomas, there is also evidence for p53 protein accumulation in early adenomas, but it is clear that p53 mutations occur mostly in the stage of late adenoma or carcinoma. The causes of the protein accumulation in the earlier stages are not clear. Strategies for early diagnosis based on detecting p53 mutations in body fluids including sputum, urine, and stool have been published (Sidransky D. J. Natl Cancer Inst 1994; 86:995-956). Although substantial technical hurdles remain, the high frequency and early occurrence of these mutations make the p53 tumor suppressor gene an attractive target for early detection and early therapeutic intervention in many common human cancers.