Retinoids, which include natural vitamin A (retinol) and its esters and synthetic analogues, are the best-studied class of agents in chemoprevention. There are more than 4,000 different retinoids which have a wide spectrum of preclinical activities, structures, pharmacological profiles, tissue distributions, receptor specificities, and toxicities. A number of retinoids have significant activity in many in vivo experimental systems including skin, bladder, lung, breast and oral carcinogenesis. In clinical trials, several retinoids have achieved significant activity in the reversal of head and neck, skin, and cervical premalignancy, and in the prevention of second primary tumors associated with head and neck, skin, and non-small cell lung cancer. Since 1984, our group has conducted a series of clinical trials to explore the chemopreventive potential of 13-cis-retinoic acid (13cRA) in the aerodigestive tract. We have conducted two consecutive randomized studies in subjects with premalignant lesions of the oral cavity. These studies showed that high-dose 13cRA alone can achieve significant short-term reversal of oral premalignancy, and that high-dose followed by low-dose 13cRA can maintain suppression of oral carcinogenesis. Three other randomized trials have confirmed significant retinoid activity in this human carcinogenic system. We also developed a randomized, placebo-controlled trial of adjuvant high-dose 13cRA in patients with head and neck cancer. Second primary tumor development was significantly decreased in the 13cRA group, but 13cRA had no impact on primary disease recurrence or survival. This presentation will update the current status of clinical trials and correlative laboratory studies of potential intermediate endpoint biomarkers in retinoid chemoprevention of aerodigestive tract carcinogenesis.