Fragile X syndrome, the most common genetic cause of autism, arises from the loss of fragile X mental retardation protein (FMRP). Jung et al. found that FMRP-null mice are deficient in a form of metabotropic glutamate receptor 5 (mGluR5)-dependent long-term depression that occurs in the ventral striatum and prefrontal cortex. Loss of FMRP in these regions disrupted a protein complex that couples the production of the endocannabinoid 2-arachidonoylglycerol (2-AG) to mGluR5 activation. Enhancing 2-AG signalling reversed certain behavioural deficits in FMRP-null mice, indicating that this complex may be a candidate drug target.