The overall objective of this dissertation was to investigate the genetic and molecular mechanisms of host response to porcine reproductive and respiratory syndrome (PRRS) virus (PRRSV), and to identify biomarkers in pigs to improve host response to PRRS and reduce PRRSV persistence in pigs. Because pigs that are only infected with PRRSV rarely exist in the industry, host transcriptome responses to vaccination with a PRRS modified-live virus (MLV) and to co-infection with PRRS and porcine circovirus type 2b (PCV2b), with or without prior, were also investigated. The first study reported in this dissertation was designed to investigate mechanisms of PRRSV persistence in nursery pigs by studying the tonsil transcriptome at 42 days post infection (dpi) with one of two PRRSV isolates, NVSL-97-7895 (NVSL) and KS-2006-72109 (KS06), along with the effect of PRRSV level in tonsil at 42 dpi and of genotype at a genetic marker (WUR) for the GBP5 resistance gene on the tonsil transcriptome at 42 dpi. Consistent with our hypotheses that (1) the more virulent NVSL PRRSV isolate inhibited host immunity in tonsil more, or activated it less, than the KS06 PRRSV isolate; (2) having a higher virus level in tonsil induces stronger immune response; and (3) pigs with the favorable AB genotype at the WUR genetic marker, which can putatively produce functional GBP5 protein, can induce a stronger innate immune response than AA pigs, the tonsil transcriptome results showed that genes related to immune response were expressed more in tonsils of KS06-infected pigs, in pigs with high tonsil viral level, and in pigs with the AB genotype at WUR, than in NVSL-infected pigs, in pigs with low tonsil viral level, and in pigs with the AA genotype at WUR, respectively. The second study was designed to investigate the effects of PRRS vaccination and WUR genotype on the blood transcriptome of nursery pigs following PRRS-MLV vaccination and to co-infection with PRRSV and PCV2b with or without prior vaccination. Consistent with our hypotheses, before co-infection, PRRS vaccination stimulated host immune response, especially innate immunity at the early stage of vaccination; after co-infection, vaccinated pigs had a stronger adaptive immunity than non-vaccinated pigs, based on higher expression levels of adaptive immunity genes and larger enrichment scores of adaptive immune cells, while non-vaccinated pigs had a stronger innate immunity than vaccinated pigs, including higher expression of innate immune response genes and larger enrichment scores of innate immune cells in blood. These findings are consistent with co-infection being the first exposure to PRRSV for non-vaccinated pigs but second exposure for vaccinated pigs, while co-infection 28 days after vaccination provides sufficient time to stimulate the adaptive immune response. These two transcriptome studies in tonsil and blood also highlighted the importance of measuring cell enrichments when evaluating transcriptomics in a multicellular tissue to more comprehensively understand transcriptome responses. The objective of the final study was to evaluate the effects of natural variants in the CD163 gene (gene edited pigs lacking CD163 are completely resistant to PRRSV) and in several other candidate genes on host response to PRRSV infection and to PRRSV/PCV2b co-infection. Results from this study showed that several SNPs in these candidate genes were significantly associated with PRRSV and PCV2b viral load following infection, and with average daily gain before and post PRRSV-PCV2b co-infection. The effects of some SNPs depended on previous vaccination for PRRS or genotype at the WUR SNP. The identified SNPs are potential genetic markers to select for increased natural resistance to PRRSV and/or PCV2. In conclusion, the work described in this dissertation has the improved knowledge of the molecular basis for host response to PRRSV infection and to co-infection with PRRSV and PCV2b, and identified genes and SNPs associated with host response. Future work is needed to confirm the impact on PRRSV resistance of the identified candidate genes and pathways on PRRSV resistance. In addition, the information uncovered in this dissertation may provide leads for the design of new vaccines to control viral disease in pigs.