Nuclear receptors (NR) are ligand-regulated transcription factors that control the expression of target genes involved in a range of physiological processes such as development, metabolism, and immunity. The retinoic acid receptor-related orphan receptors alpha, beta, and gamma (RORA, RORB, and RORC) comprise a distinct subfamily of nuclear receptors and are considered 'orphan' receptors, as they have no known generally agreed upon endogenous ligands, although these receptors do bind to and are modulated by oxysterols. Several recent reports have highlighted the potential role for RORs in human disease, and more importantly, studies have demonstrated that these receptors can be modulated by exogenous synthetic ligands. The identification of potent and selective ROR ligands will allow for a better understanding of the roles of the ROR receptors in human disease, and potentially pave the way for development of novel therapeutics. Here we review the current status of synthetic ligand development from both the primary and patent literature.