Orally administered retinoids can be associated with significant adverse effects because of high systemic exposure and a lack of receptor selectivity. Targeting the diseased tissue and improving the selectivity of the retinoid-receptor interaction to activate only those discrete pathways required for efficacy may minimize adverse effects. First- and second-generation retinoids contain several alternating single and double bonds that confer great conformational flexibility, allowing the molecules to adopt a variety of shapes and creating the potential to interact with multiple receptors. We hypothesized that, by designing a more rigid conformational structure, the receptor selectivity of retinoids could be improved and their therapeutic index enhanced. This strategy has resulted in the development of tazarotene. The receptor selectivity of tazarotene, together with its topical delivery, ensures a targeted action on psoriatic keratinocytes. (J Am Acad Dermatol 1998;39:S124-8.)