The witchweeds, members of the genus Striga, are noxious and persistent pests in farmers' fields and serious constraints to crop productivity throughout Africa, India, and Southeast Asia. Among the primary hosts for Striga are the major cereals (maize, sorghum, rice, and millet) and grain legumes (cowpea) that are important food staples worldwide. The negative impact of parasitic plants on crop productivity increases globally each year, and their potential for affecting domestic agriculture looms larger as the movement of seed resources expands on a global scale. At the present time there is a limited understanding of how Striga and other parasitic plants select a suitable host and overcome the innate defense responses of the host in order to complete their life-cycle. In the grasses most reported resistance to Striga appears to be polygenic with a large genotype by environment interaction. In contrast, resistance to S. gesnerioides in cowpea is conferred by single dominant genes functioning in a race-specific manner suggesting that a gene-for-gene mechanism similar to effector-triggered immunity (ETI) described in other host–pathogen interactions is likely operating in these parasite-host associations. A hallmark of ETI is the direct or indirect recognition of parasite-derived avirulence (Avr) factors and other effectors that interfere with plant innate immunity by host sensors (or R proteins) leading to activation of defense responses. The recent cloning and functional characterization of a race-specific R gene from cowpea encoding a canonical coiled-coil (CC)-nucleotide binding site (NBS)-leucine-rich repeat (LRR) type R-protein opens the door for further exploration of the mechanism of host resistance and provides a focal point for studies aimed at uncovering the molecular and genetic factors underlying parasite virulence and host selection. The potential for the development of novel strategies for parasite control and eradication based on parasite virulence factors is discussed.