Background: The superfamily of nuclear receptors (NRs) comprises ligand-gated and ligand-independent transcription factors, modulating genetic programs mostly by binding to specific DNA elements. NRs not only control many aspects of cellular homeostasis but also play crucial roles in numerous human diseases. As the activity of NRs can be modulated by small molecules, these are successfully used in the clinics for the treatment of metabolic and cardiovascular diseases as well as cancer. Objective/methods: This review provides an overview on the molecular classification and disease relevance of NRs, as well as on recent advances in pharmacologic (pre)clinical targeting approaches and patent applications. Patent, drug approval and bibliographic searches were carried out using various databases and websites, including Freepatentsonline, CenterWatch Clinical Trials Listing Service and the PubMed database. Results/conclusion: To fully exploit and market the tremendous potential of NRs for the treatment of human diseases, a systematic understanding of the structure–function relationship of NRs is urgently needed. Novel insights into the network of NR biology together with the recent advancements in medicinal chemistry may lead to novel therapeutics with improved efficacy, selectivity and safety.