Black shank root and crown rot disease caused by the soil-borne pathogen, Phytophthora nicotianae, is detrimental to commercial tobacco (Nicotiana tabacum) production and is responsible for significant economic loss. Numerous naturally occurring alleles for resistance to black shank have been utilized to increase resistance in current commercial varieties. Due to a possible emergence of resistance breaking strains, novel mechanisms of resistance need to be investigated. Loss of susceptibility is a durable mechanism of resistance involving the removal of genes beneficial to the infecting organism, thereby decreasing the susceptibility of the crop. This approach relies on finding proteins in the plant that are bound by certain virulence factors. In this study, an effectoromics approach was used to determine possible susceptibility genes in tobacco. Conserved virulence genes were identified using a combination of genome sequencing and transcriptomics. Twenty-nine reference quality genomes from different isolates of P. nicotianae were assembled and used to determine gene expression of virulence factors during infection. A comparative genomic analysis coupled with RNA-Seq identified 50 conserved virulence genes. These were tested for their ability to increase the virulence of Phytophthora utilizing a leaf infiltration assay. Eight high-impact targets were then used to capture proteins that interact with these virulence factors as possible susceptibility genes. This analysis yielded several putative susceptibility genes which could be interrogated as targets for novel black shank resistance, independent of any existing genetics.