It is well known that the steroid hormone glucocorticoid and its nuclear receptor regulate the inflammatory process, a crucial component in the pathophysiological process related to human diseases that include atherosclerosis, obesity and type II diabetes, inflammatory bowel disease, Alzheimer's disease, multiple sclerosis, and liver tumors. Growing evidence demonstrates that orphan and adopted orphan nuclear receptors, such as peroxisome proliferator-activated receptors, liver x receptors, the farnesoid x receptor, NR4As, retinoid x receptors, and the pregnane x receptor, regulate the inflammatory and metabolic profiles in a ligand-dependent or -independent manner in human and animal models. This review summarizes the regulatory roles of these nuclear receptors in the inflammatory process and the underlying mechanisms.