Nuclear hormone receptors act as transcription factors that can be activated by ligands of either endogenous or exogenous origin. Pharmacological ligands acting via nuclear hormone receptors have been exceptionally succesful in the treatment of skin disease, among them glucocorticoids, retinoids and vitamin D analoga. New opportunities arise from targeting Perioxisome Proliferator-Activated Receptors (PPAR), Liver X Receptors (LXR) and the Pregnane X Receptor (PXR). These receptors exhibit anti-inflammatory activities and modulate additional aspects of cutaneous physiology including differentiation, energy-, lipid-, and cytochrome metabolism. Ligands of PPAR, LXR and PXR have beneficial effects on skin homeostasis and may represent promising targets for future therapeutic approaches in dermatology.