Nuclear receptors (NRs) comprise one of the most abundant classes of transcriptional regulators of metabolic diseases and have emerged as promising pharmaceutical targets. Small heterodimer partner (SHP; NR0B2) is a unique orphan NR lacking a DNA-binding domain but contains a putative ligand-binding domain. SHP is a transcriptional regulator affecting multiple key biological functions and metabolic processes including cholesterol, bile acid, and fatty acid metabolism, as well as reproductive biology and glucose-energy homeostasis. About half of all mammalian NRs and several transcriptional coregulators can interact with SHP. The SHP-mediated repression of target transcription factors includes at least three mechanisms including direct interference with the C-terminal activation function 2 (AF2) coactivator domains of NRs, recruitment of corepressors, or direct interaction with the surface of NR/transcription factors. Future research must focus on synthetic ligands acting on SHP as a potential therapeutic target in a series of metabolic abnormalities. Current understanding about the pleiotropic role of SHP is examined in this paper, and principal metabolic aspects connected with SHP function will be also discussed.