The vanilloid receptor (TRPV1 or VR1), widely distributed in the central and peripheral nervous system, is activated by a broad range of chemicals similar to those implicated in Multiple Chemical Sensitivity (MCS) Syndrome. The vanilloid receptor is reportedly hyperresponsive in MCS and can increase nitric oxide levels and stimulate N-methyl-D-aspartate (NMDA) receptor activity, both of which are important features in the previously proposed central role of nitric oxide and NMDA receptors in MCS. Vanilloid receptor activity is markedly altered by multiple mechanisms, possibly providing an explanation for the increased activity in MCS and symptom masking by previous chemical exposure. Activation of this receptor by certain mycotoxins may account for some cases of sick building syndrome, a frequent precursor of MCS. Twelve types of evidence implicate the vanilloid receptor as the major target of chemicals, including volatile organic solvents (but not pesticides) in MCS.