The three retinoic acid receptors (RARα, β, and γ) have distinct roles, so retinoid-based therapies need isoform-selective compounds. This review by Powała et al. focuses on RARγ, which helps maintain stem cells is overexpressed in many cancers. It describes how selective RARγ agonists and antagonists were designed, and how agonists bind the receptor’s ligand-binding domain, drawing on crystal structures and docking studies. These interactions are key to selectivity and potency, and they can guide the design of new compounds. Selective RARγ agents show therapeutic potential in cancer, psoriasis, heterotpic ossification, and acne. In vitro, an RARγ antagonist kills cancer stem cells and avoids the side effects of all-trans retinoic acid. No crystal structure yet exists for RARγ bound to an antagonist such as AGN205728, so the authors propose that new antagonists be designed using docking and binding free energy calculations.