Retinoic acid receptors (RAR), thyroid hormone receptors (TR), peroxisome proliferator activated receptors (PPARs) and the orphan receptor, LXR, bind preferentially to DNA as heterodimers with a common partner, retinoid X receptor (RXR), to regulate transcription(1-6). We investigated whether RXR-selective agonists replicate the activity of ligands for several of these receptors! We demonstrate here that RXR-selective ligands (referred to as rexinoids) function as RXR heterodimer-selective agonists, activating RXR : PPAR gamma and RXR:LXR dimers but not RXR:RAR or RXR:TR heterodimers. Because PPAR gamma is a target for antidiabetic agents, we investigated whether RXR ligands could alter insulin and glucose signalling. In mouse models of noninsulin-dependent diabetes mellitus (NIDDM) and obesity, RXR agonists function as insulin sensitizers and can decrease hyperglycaemia, hypertriglyceridaemia and hyperinsulinaemia, This antidiabetic activity can be further enhanced by combination treatment with PPAR gamma agonists, such as thiazolidinediones. These data suggest that the RXR:PPAR gamma heterodimer is a single-function complex serving as a molecular target for treatment of insulin resistance, Activation of the RXR:PPAR gamma dimer with rexinoids may provide a new and effective treatment for NIDDM.