Vitamin A is essential for development and differentiation of multiple tissues. Its derivatives, the retinoids, are potent drugs used to treat and prevent a variety of diseases. Retinoid effects are mediated by retinoic acid receptors (RARs) and retinoid X receptors (RXRs). There are three known RARs (α, β, and γ), and multiple isoforms of each receptor exist. Many of the therapeutic effects of retinoids including cancer chemoprevention and treatment of dermatologic disorders are mediated through RARβ. In humans, five isoforms of this gene have been described. Specific isoforms of RARβ exert distinct and sometimes opposing functions by altering patterns of target gene induction. Functional isoforms that activate distinct cassettes of target genes with differing biologic consequences include RARβ1 and RARβ2. Dominant negative isoforms of this gene that inhibit target gene activation include RARβ4 and RARβ5. RARβ1 is poorly understood although this may function as an oncogene in certain cancers. Chromatin modifying drugs have been shown to trigger isoform-specific changes in the RARβ gene. This review focuses on the structure and function of RARβ isoforms as well as recent work in the epigenetic targeting of specific RARβ isoforms. Discerning isoform-specific functions will be critical for exploiting the full potential of retinoid-based therapy including rational approaches to combining retinoids with chromatin modifying drugs.