Numerous members of the nuclear hormone receptor (NR) superfamily have been demonstrated to regulate metabolic function in a cell- and tissue-specific manner. This review brings together recent studies that have associated members of the NR superfamily, the orphan NR4A subgroup, with the regulation of metabolic function and disease. The orphan NR4A subgroup includes Nur77 (NR4A1), Nurr1 (NR4A2), and Nor-1 (NR4A3). Expression of these receptors is induced in multiple tissues by a diverse range of stimuli, including stimuli associated with metabolic function, such as: β-adrenoceptor agonists, cold, fatty acids, glucose, insulin, cholesterol, and thiazolidinediones. In vitro and in vivo gain- and loss-of-function studies in major metabolic tissues (including skeletal muscle, adipose, and liver cells and tissues) have associated the NR4A subgroup with specific aspects of lipid, carbohydrate, and energy homeostasis. Most excitingly, although these orphan receptors do not have known endogenous ligands, several small molecule agonists have recently been identified. The preliminary studies reviewed in this manuscript suggest that therapeutic exploitation of the NR4A subgroup may show utility against dyslipidemia, obesity, diabetes, and cardiovascular disease.