Seven races of Striga gesnerioides parasitic on cowpea, a major food and forage legume in sub-Saharan Africa, have been identified. Race-specific resistance of cowpea to Striga involves a coiled-coil nucleotide binding site leucine-rich repeat domain resistance protein encoded by the RSG3-301 gene. Knockdown of RSG3-301 expression by virus-induced gene silencing in the multirace-resistant cowpea cultivar B301 results in the failure of RSG3-301-silenced plants to mount a hypersensitive response and promotes parasite necrosis when challenged with Striga race SG3, whereas the resistance response to races SG2 and SG5 is unaltered. Our findings indicate that a gene-for-gene resistance mechanism is operating in these unique plant-plant associations.