Pathogens can elicit high selective pressure on hosts, potentially altering genetic diversity over short evolutionary timescales. Intraspecific variation in immune response is observable as variable survivability from specific infections. The great gerbil (Rhombomys opimus) is a rodent plague host with a heterogenic but highly resistant phenotype. Here, we investigate the genomic basis for plague-resistant phenotypes by exposing wild-caught great gerbils to plague (Yersinia pestis). Whole genome sequencing of 10 survivors and 10 moribund individuals revealed a subset of genomic regions showing elevated differentiation. Gene ontology analysis of candidate genes in these regions demonstrated enrichment of genes directly involved in immune functions, cellular metabolism and the regulation of apoptosis as well as pathways involved in transcription, translation, and gene regulation. Transcriptomic analysis revealed that the early activated great gerbil immune response to plague consisted of classical components of the innate immune system. Our approach combining challenge experiments with transcriptomics and population level sequencing, provides new insight into the genetic background of plague-resistance and confirms its complex nature, most likely involving multiple genes and pathways of both the immune system and regulation of basic cellular functions.