The overall objective of this thesis was to identify the role of host genetics in susceptibility to viral disease in pigs, using experimental infection with porcine reproductive and respiratory syndrome (PRRS) virus (PRRSV). Co-infection with PRRS virus (PRRSV) and porcine circovirus type 2b (PCV2b) was also investigated, since pigs are rarely infected with PRRSV alone. The study reported in the first chapter was designed to investigate the role of host genetics in response to PRRSV-infection in pigs divergently selected for feed efficiency. Contrary to our hypothesis that the more feed efficient pigs would be more susceptible to disease as a correlated response, results showed that the feed efficient pigs were less affected by the PRRS challenge. Subsequent studies were designed to further investigate the role of host genetics in response to PRRSV-infection by estimating the effect of the guanylate binding protein 5 (GBP5) region (the putative causative gene for a major quantitative trait locus for host response to PRRS) on PRRS vaccination response and host response to PRRSV/PCV2b co-infection. Additional objectives were to identify regions other than GBP5 associated with vaccination and co-infection and regions with a significantly different effect on co-infection response, depending on previous vaccination for PRRS. Results from these studies showed that the GBP5 region had a significant effect on PRRS vaccination viral load (VL), PRRS VL, and PCV2b VL (for pigs previously vaccinated against PRRSV). Regions other than GBP5 were not significantly associated with vaccination VL or PRRS VL, but several single nucleotide polymorphisms (SNPs) near the major histocompatibility complex were significantly associated with PCV2b VL. Multiple SNPs were also associated with growth rate following vaccination and co-infection, including two SNPs with a significantly different effect on growth, depending on previous vaccination for PRRS. Another objective was to assess the ability of genomic prediction using SNPs within the GBP5 region only versus SNPs across the genome versus SNPs outside of the GBP5 region to predict: 1) host response to PRRSV/PCV2b co-infection when using a PRRSV-only infected training population and 2) host response to infection with a field isolate of PRRSV (by PRRSV-only infection or PRRSV/PCV2b co-infection) using a PRRS vaccinated training population. Results from this study showed that using SNPs within the GBP5 region had moderate predictive ability for VL traits, but low to no predictive ability for growth rate in an unrelated, co-infected population. Collectively, these studies further validated the effect of the GBP5 region on host response to PRRS. However, prior to this thesis, little was known regarding the effect of the GBP5 region on economically important traits under non-challenged conditions. Therefore, the final objective was to estimate the effect of the GBP5 region on traits under selection in commercial pigs under non-challenged conditions. Results showed that few significant associations with the GBP5 region were detected and the magnitude of the effects that were identified were not large enough to be practically relevant. In addition, no effect of the GBP5 region on overall selection index value was identified. To conclude, the GBP5 region was significantly associated with VL traits following vaccination and co-infection and can be used to predict host response to PRRSV-only infection or co-infection with moderate predictive ability. However, using SNPs across the genome had superior predictive ability for growth rate, which agrees with the non-significant effect of the GBP5 region on growth post co-infection. Therefore, pre-selection for the GBP5 region, followed by selection based on genomic estimated breeding value for growth rate following PRRSV-infection is a promising PRRS control strategy that can be used to breed pigs for improved host response to PRRS.