Porcine reproductive and respiratory syndrome virus (PRRSV) is arguably the most economically important swine pathogen worldwide. The current available vaccines were generally effective against homologous strains but were less effective or ineffective against heterologous strains. Given the degree of genetic diversity observed among PRRSV strains, it is not surprising to see that the current vaccines, which are all based on a single strain, do not confer effective protection against heterologous field strains. The effectiveness of a vaccine against heterologous strains will largely depend on the genetic relatedness of the virus strain to which the vaccinated animals were exposed. The observed genetic diversity among field isolates will continue to be the major obstacle for PRRSV control. Therefore, the design of future vaccines must take into consideration the genetic diversity of PRRSV. Here we describe the development of novel modified live-attenuated vaccines (MLV) and subunit protein vaccines against PRRSV by using cutting-edge molecular breeding and DNA shuffling technologies. We have successfully constructed an infectious cDNA clone of a North American strain (strain ATCC VR2385) of PRRSV, and developed an improved DNA-launched reverse genetics system for PRRSV. By using the PRRSV reverse genetic systems, we demonstrated that we can successfully breed the major envelope protein gene GP5 from 5 genetically different strains of PRRSV and rescue infectious chimeric viruses. The rescued chimeric virus is a good candidate for a MLV. In addition, the shuffled chimeric GP5 along with shuffled chimeric M, GP3 and GP4 genes can serve as an improved subunit protein vaccine against PRRSV as well.