Macrophages play diverse roles in host defense and in maintenance of homeostasis. Based on their ability to promote inflammatory responses, inappropriate macrophage function also contributes to numerous pathological processes, including atherosclerosis, rheumatoid arthritis and inflammatory bowel disease. Members of the nuclear receptor superfamily of ligand-dependent transcriptions factors have emerged as key regulators of inflammation and lipid homeostasis in macrophages. These include the glucocorticoid receptor (GR), which inhibits inflammatory programs of gene expression in response to natural corticosteroids and synthetic anti-inflammatory ligands such as dexamethasone. Also, in response to endogenous eicosanoids and oxysterols, respectively, peroxisome proliferator-activated receptors (PPARs) and liver X receptors (LXRs) regulate transcriptional programs involved in inflammatory responses and lipid homeostasis. Identification of their mechanisms of action should help guide the development of new therapeutic agents useful in the treatment of diseases in which macrophages play critical pathogenic roles.