We report the application of RNA- sequencing technology for high-throughput profiling of histone modifications in mammalian cellsor identification of expressed genes upon infection by Spongospora subterranea. Using RNA-sequencing (RNA-seq), 2058 differentially expressed genes (DEGs) were identified from two potato cultivars (tolerant and susceptible) in response to Sss infection. Analysis of the expression patterns of ten selected defense-response genes was carried out at two different stages of tuber growth using RT-qPCR to validate the RNA-seq data. Several defense related genes showed contrasting expression patterns between the tolerant and susceptible cultivars, including marker genes involved in the salicylic acid hormonal response pathway (StMRNA, StUDP and StWRKY6). Induction of six defense related genes (StWRKY6, StTOSB, StSN2, StLOX, StUDP and StSN1) persisted until harvest of the tubers, while three other genes (StNBS, StMRNA and StPRF) were highly up-regulated during the initial stages of disease development. The results of this study suggested that the tolerant potato cultivar employs quantitative resistance and salicylic acid pathway hormonal responses against tuber infection by Sss. The identified genes have the potential to be used in the development of molecular markers for selection of powdery scab resistant potato lines in marker assisted breeding programs. Overall design: Examination of 2 different potato cultivars, inoculated and un-inoculated with Spongospoora subterranea.