Spongospora subterranea is an obligate biotrophic pathogen, causing a tremendous economic loss in the potato industry. Currently, there are no effective chemical or biological strategies for the control of S. subterranea. Understanding the gene regulation of pathogens in their host is dependent on multidimensional datasets. To further our understanding of S. subterranea biology during infection, we characterized the transcriptome and proteome of the pathogen inside the susceptible and resistant potato cultivars. A total of 7650 transcripts from S. subterranea were identified in the transcriptome analysis in which 1377 transcripts were differentially expressed between two cultivars. In proteome analysis, we identified 117 proteins with 14 proteins significantly changed in comparison between resistant and susceptible cultivars. The transcriptome analysis uncovered the gene regulatory modules underlying virulence. The functional annotation of transcriptome data indicated that the gene ontology terms related to the transportation and actin processes were induced in the resistant cultivar. The downregulation of enzyme activity and nucleic acid metabolism in the resistant cultivars suggesting a remarkable influence of these processes in the virulence of S. subterranea. The protein analysis results indicated that the majority of identified proteins were related to the metabolic processes. The present study provides a comprehensive molecular insight into the multiple layers of gene regulation that contribute to S. subterranea germination and growth in planta and illuminates the role of host immunity in affecting pathogen responses.