Transformation of wild species into elite cultivars through domestication entails narrowing the genetic diversity in crop plants. For sorghum in Eastern and Central Africa, continued selection has greatly contributed to sorghum with a higher susceptibility to the parasitic weed Striga, as well as an increased virulence of the parasite itself. An efficient strategy to build new resistance against Striga in cultivated sorghum is to reclaim resistance lost during domestication, while preventing increasing virulence from the parasite. Our goal is to expand the genetic basis of cultivated sorghum to cope with evolving Striga virulence in order to build durable and broad-spectrum resistance. To achieve this we have firstly, screened the resistance of wild sorghum for Striga resistance and determined differential gene expression in resistant and susceptible sorghum using RNA sequencing; secondly, we have screened a core selection of sorghum accessions selected to represent the global sorghum diversity (reference set) for Striga resistance and conducted genome wide association mapping to identify Striga resistance loci; and thirdly predicted Striga proteins that may act as effectors aiding Striga to evade, and subsequently overcome the host’s resistance. We found that wild sorghum accessions are resistant to Striga parasitism by various mechanisms; mostly through mechanical barriers on the cell wall or by deposition of secondary metabolites at the interphase of the host and parasite. Transcriptome profiling of Striga resistant wild sorghum affirm this finding based on the functions of differentially expressed genes. Pathways involved in secondary metabolite responses; cell wall modification and resistance were unregulated in resistant wild sorghum. Our GWAS analysis further affirms the importance of the aforementioned pathways in mediating host defense.