The genomes of nidoviruses are infectious, and virus replication is initiated as the genome is delivered to the cytoplasm and the replicase is translated by the host cell ribosomes. Nidovirus reverse-genetics systems are needed to better understand aspects of their complex replication strategy, pathogenesis, and mechanisms of host range expansion, and for the generation of safe and effective antiviral therapies. As the majority of existing research into the mechanisms of nidovirus host range expansion has been completed in coronavirus models, this chapter is devoted to coronaviruses. Although nidoviruses have the opportunity to expand their host ranges, they must be able to exploit such opportunities by rapidly adapting to fit their new host. Nidoviruses can explore the range of viable genetic variation through two mechanisms, mutation and recombination. Reverse-genetics systems allow viral genomes to be directly manipulated and linked to a given phenotype. A more recently described approach cloned the full-length genome into poxvirus vectors. All three of these systems, targeted RNA recombination, full-length infectious cDNA expressed in stable amplification systems, and infectious clones amplified as multicomponent cDNAs, are currently used in research and have relative strengths. The biology of nidoviruses makes them significant threats as existing, emerging, and reemerging pathogens.