Certain retinoids (compounds that comprise the vitamin A group of compounds, their derivatives, and their analogues) have demonstrated a prophylactic and, in some cases, a therapeutic effect on preneoplastic lesions and carcinogen-induced malignancies in vivo. Cancers of the bladder, breast, and skin are among the malignancies that are inhibited or suppressed by certain retinoids. During the early studies in vivo of the caner chemopreventive effects of retinoids, retinyl methyl ether (RME) was shown to suppress carcinogen-induced mammary cancer. However, RME is demethylated in vivo and in vitro to retinol (vitamin A) by microsomal oxidases, and it was assumed that retinol was responsible for the observed chemopreventive activity of RME. Retinyl butyl ether and the 2,3,6-trimethyl-4-methoxyphenyl (TMMP) analogue of RME were reported to be ineffective in similar studies of mammary carcinogenesis. Therefore, it appeared that retinyl ethers either would not inhibit mammary carcinogenesis or would be active only if they were converted to retinol. Pharmacological doses of retinol cause unacceptable increases of retinyl esters in the liver and produce toxic effects. Consequently, investigation of retinyl ethers as cancer chemopreventive agents practically ceased. A rationale - based on reported biological activities of RME in vitro and a careful analysis of reported pharmacokinetic data - for resuming studies of retinyl ethers was developed (Shealy, Preventive Medicine, 1989, 18, 624-645). It was postulated that new retinyl ethers could be found that would not be subject to the action of microsomal oxidases, would accumulate in mammary tissue, would inhibit mammary carcinogenesis, and would be less toxic than retinyl acetate (the reference retinoid for suppression of mammary cancer). New retinyl ethers were synthesized in our laboratories and bioassayed. Retinyl 2-propynyl ether (RPE), a member of the initial group of new retinyl ethers, inhibited the development of mammary cancer in rats and caused a much lower level of retinyl palmitate in the liver than did retinyl acetate. RPE was shown to undergo an intramolecular Diels-Alder reaction, a type of reaction not previously reported for the retinoid side chain. Retinyl 3,4,5-trimethoxybenzyl ether (RTMBE), a member of the second group of new retinyl ethers, accumulated in mammary tissue, was not converted to retinol by microsomal oxidases, markedly decreased the incidence of MNU-induced mammary adenocarcinomas in rats, did not cause significant increases in retinyl palmitate in the liver, and was not toxic at high doses. Thus, the original postulates have been verified, and retinyl ethers appear to be worthy of further development as potential cancer chemopreventive agents. Preliminary studies indicate that retinyl ethers may have a previously unidentified mechanism of action; they may act by inhibiting activator protein 1 (AP-1) activity.