In previous studies, A. gambiae showed electroantennogram responses to indole originating from human sweat and to indole and 3methyl indole as constituents of water in breeding sites in Tanzania. Our data comprise the first instance of an A. gambiae OBP-ligand pairing and the first time that electrophysiology and dsRNA-mediated inhibition of gene expression are combined to confirm a ligand recognition pathway mediated by a specific OBP in mosquitoes. These results demonstrate the importance of OBPs in the control of odor responses and delineate a general approach for analyzing olfactory-mediated behavior in medically important insects. More compelling evidence for the cooperation between OBPs and ORs comes from recent experiments in Drosophila in which perception of the volatile pheromone 11-cis vaccenyl acetate has been studied. cVA stimulates a receptor cell in T1 sensilla on the male antennae. These sensilla co-express the odorant receptor Or67d and the OBP76a encoded by the gene lush. Loss of OBP76a in lush mutants results in insensitivity to cVA, even though they properly express all ORs. Mutants that lack T1 sensilla also lack Or67d and do not respond to cVA, but the cVA response can be restored by ectopically expressing Or67d in other sensilla if these sensilla also co-express OBP76a. Oncrasin-1 conformational changes of OBP proteins upon ligand binding appear to alter their structure in such a way that the receptor can distinguish between the ����loaded���� and ����empty���� form of the OBP. In fact, mutations in OBP76a that mimic the conformational shift caused by ligand binding can activate the olfactory response in the absence of cVA. In a given sensillum, OBPs may contribute to the specificity of odor reception by exhibiting a binding preference for certain odor molecules thus selecting which odors to transport. As is the case with the in vitro binding of indole to AgamOBP1, ligand-binding specificities for OBPs with dissociation constants in the mM range have been previously established. While PBPs often show a high 10-Hydroxy-aconitine degree of specificity and can discriminate between closely related compounds, OBPs appear to recognize a broader spectrum of odorants, suggesting that odor molecules may be bound with high affinity by one class of OBPs and with a lower affinity by another class.