The rapid mutation rate of RNA viruses leads to significant genetic and antigenic variation. This diversity presents great challenges for the development of effective vaccines and treatments. These challenges highlight the need for a better understanding of the molecular mechanisms underlying antigenic variation and alternative treatment strategies. While significant research to address these problems has been undertaken in human diseases, less is known about these processes in many veterinary diseases, including the economically significant porcine reproductive and respiratory syndrome virus (PRRSV). Although immune selection has been a proposed mechanism for the diversity in PRRSV and its continual circulation within and between herds, direct evidence of immune escape variants arising during the course of infection in vivo has never been shown. To examine the role of immune selection and escape during PRRSV infection, we examined genetic and antigenic variation of PRRSV using retrospective, sequential samples from five experimentally infected pigs with differing virological and immunological outcomes, including three pigs that experienced a rebound in viremia, suggesting viral escape from host immune control. Sequence analyses revealed limited genetic variation during acute PRRSV infection. However, distinct envelope protein-encoding ORF2-6 haplotypes were identified in each pig’s late day virus. Chimeric viruses containing all or part of predominant ORF2-6 haplotypes were tested in virus neutralization assays using autologous sera, and in four viruses, genetic variation in ORF2-6 resulted in antigenic variation and immune escape. Immune escape mapped to multiple envelope proteins, including GP5 and/or GP2, GP3, and GP4 and usually, but not always, required a combination of amino acid changes. Importantly, the key amino acid changes and/or combination of changes that mediated escape differed by pig and by virus haplotype. To test if the mutations that mediated immune escape resulted in a reduction in replication fitness of the viruses, we performed a series of infectivity and replication kinetics assays using the escape variants and the parental virus. Our results showed that one of the four escape variants had reduced infectivity compared to the parental virus, but none of the escape variants had markedly reduced growth rates in MARC-145 cells. PRRSV pooled neutralizing antibody was found to primarily target a post-attachment, pre-genome synthesis step of replication. These data demonstrate that PRRSV envelope proteins are under immune selection that contributes to the emergence of replication-fit immune escape variants. The diverse strategies of immune escape likely contribute to difficulties in producing effective vaccines for PRRSV, and therefore alternative control strategies are needed. Antivirals have proven to be an extremely successful treatment strategy for several human viral diseases, and have the potential for use in the treatment of PRRSV. Previously, the natural compound atractylodinol was reported to have anti-PRRSV activity in vitro. Atractylodinol and fourteen analogs were synthesized and their anti-PRRSV activity was characterized in vitro. Seven of the analogs had potent inhibitory activity against 5-log10 infectious units of PRRSV at low μM concentrations. Analog compound 19 was shown to inhibit PRRSV primarily at a post-attachment step during PRRSV entry. These results provide evidence that the atractylodinol analogs are promising antiviral candidates for trials in pigs. Overall, the work from this dissertation indicates that selective pressure by the immune system contributes to the vast genetic diversity of PRRSV, and there is potential for the treatment of PRRSV outbreaks with antivirals.