Retinoids have been studied as chemopreventive agents in clinical trials. Given their ability to inhibit mammary carcinogenesis in preclinical models. Fenretinide has extensively been investigated because of its favorable toxicological profile in humans. In a phase III secondary prevention trial, fenretinide showed a trend to a reduction of second breast malignancies in premenopausal women but not in postmenopausal women. This pattern was associated with a similar modulation of circulating IGF-I. A trend towards a reduction of ovarian cancer was also noted. Biomarker studies of fenretinide or novel selective retinoids alone and in combination with different nuclear receptor ligands are being conducted. These studies provide a model for testing the safety and tolerability, pharmacokinetics and pharmacodynamics, and biomarker modulation in high-risk women, and offer clues as to both the pathophysiology of carcinogenesis and the drug mechanisms of action, and help select new compounds and doses for testing in large randomized studies.