Nuclear receptors are transcription factors that can be activated by specific ligands. Recent progress has shown that retinoid X receptor (RXR) and its heterodimerization partners, including peroxisome proliferator-activated receptors, regulate many important genes involved in energy homeostasis and atherosclerosis, and should be promising therapeutic targets of metabolic syndrome. RXR heterodimers regulate a number of complex cellular processes, and genetic studies of RXR heterodimers have provided important clinical information in addition to knowledge gained from basic research. Genetic variants of RXR heterodimers were screened and investigated, and some variants were shown to have a considerable impact on metabolic disorders, including phenotypic components of familial combined hyperlipidemia. The combined efforts of basic and clinical science regarding nuclear receptors have achieved significant progress in unraveling the inextricably linked control system of energy expenditure, lipid and glucose homeostasis, inflammation, and atherosclerosis.This review summarizes the current understanding regarding RXR heterodimers based on their human genetic variants, which will provide new clues to uncover the background of multifactorial disease, such as metabolic syndrome or familial combined hyperlipidemia.