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The natural retinoids—all-trans-retinoic acid (trans-RA) and its 9-cis isomer (9-cis-RA)—and their synthetic analogs have important functions in regulating cell proliferation, differentiation, and morphogenesis. For these reasons, retinoids are successfully used as therapeutic agents to treat several proliferative diseases, such as acne, psoriasis, skin cancer, and acute promyleoblastic leukemia, and to prevent the recurrence of head-and-neck and certain skin cancers [1-3]. Because of their ability to modulate cell differentiation and proliferation, retinoids at therapeutically effective doses may have such toxic side effects on normal cells that their use is limited [4]. A continuing goal of numerous drug development programs has been to identify therapeutically effective retinoids that have reduced systemic side effects [5] Such an approach is possible because retinoid activities are regulated through their receptor proteins.

The seco-steroid hormone 1α,25-dihydroxyvitamin D3 (VD), is the most biologically active form of vitamin D3 and an effective regulator of calcium homeostasis and bone metabolism [1]. VD has been known, for some time, to inhibit cell growth and to induce differentiation in several normal and malignant cell types [2]. Within recent years, VD has additionally been shown to induce apoptosis in human breast cancer and leukemic cell lines [3]. Similar profound effects are also known for all-trans retinoic acid (RA) and other synthetic retinoids, which are vitamin A derivatives [4,5]. VD, VD analogues and retinoids have the potential to be used in the treatment of various skin diseases, including psoriasis and acne [6], and in the treatment or chemoprevention of cancers, including melanoma that are, in general, notoriously resistant to chemotherapeutic drugs in vitro and in vivo [7].

In both hypo- as well as hyper-vitaminosis A, alterations in clinical appearance and histological morphology of the skin, although non-specific, are known to occur [1 2]. Realizing the importance of vitamin A for the normal physiology of epithelial tissue, investigative dermatologists were among the first to experiment with retinoid therapeutics [3 4]. More than three decades ago, they introduced topical retinoic acid treatment for actinic keratosis, a premalignant skin condition characterized by cytologic atypia and a loss of normal differentiation of epidermal keratinocytes. Since then, a variety of dermatological conditions, ranging from acne to photoaged skin, have proven to be responsive to topical and/or systemic retinoid treatment [5]. In addition to the impressive clinical advances that have been made with retinoid therapy, there have also been significant advances in our understanding of the cutaneous effects of retinoids. Indeed, skin remains the only human tissue in which systematic analyses of retinoid biology have been made under in vivo conditions. This chapter summarizes the relevant data, emphasizing the in vivo studies on human skin that form the basis of prevailing knowledge about metabolism and molecular mechanisms of retinoid action.