Porcine reproductive and respiratory syndrome (PRRS) is one of the most challenging subjects of research in veterinary viral immunology, and the immune response against PRRS virus (PRRSV) still is poorly understood. Infected pigs develop a strong and rapid humoral response but these initial antibodies do not confer protection and can even be harmful by mediating an antibody-dependent enhancement of disease. In contrast, development of neutralising antibodies (NAs) is delayed and generation of cell-mediated immune responses, such as PRRSV-specific interferon (IFN)-gamma secreting cells, is initially erratic. In spite of this, induction of strong and rapid NAs and IFN-gamma responses seem to be required for effective vaccination. PRRSV strongly modulates the host's immune responses. The virus inhibits key cytokines, such as IFN-alpha, and may induce regulatory cytokines, such as interleukin (IL)-10. Development of NAs seems to be impaired by the existence of a decoy epitope close to the main neutralisation epitope in glycoprotein 5. This ability to modulate the host immune response probably varies among strains or isolates. The genetic diversity of the virus is very high and it has been shown that this diversity can have serious implications for the development of vaccines, since the immunity induced by one strain may be only partial against a different strain, even within the same genotype. With this panorama, the development of newer and universally efficacious PRRSV vaccines is challenging, but the present state of knowledge allows optimism if collaborative efforts are undertaken in the scientific community.