Salmonella is a major foodborne pathogen, responsible for approximately 1.35 million cases of foodborne illness each year in the United States. There are more than 2,600 serovars within the genus Salmonella, which can be divided into two major categories based on the disease they cause: typhoidal serovars (e.g., Salmonella enterica subsp. enterica serovar [“S.”] Typhi) cause typhoid fever, while nontyphoidal serovars (e.g., S. Typhimurium) typically cause a self-limiting gastroenteritis. Furthermore, Salmonella serovars differ in their host ranges and virulence, as some serovars, like S. Typhimurium, can cause disease in a multitude of hosts, while others, like S. Gallinarum, only cause disease in a single host.The studies presented here provide important insight on host adaptation and virulence of Salmonella in multiple relevant areas, by: (1) Emphasizing the importance of serovar- and subtype-level regulations as policy options to control human salmonellosis cases; (2) utilizing comparative transcriptomics to better characterize diverse nontyphoidal Salmonella (NTS) serovars; and (3) applying genomic analyses to elucidate evolutionary mechanisms leading to host adaptation and virulence attenuation, using S. Cerro as an example. The results of these studies provide understanding of host specificity in Salmonella with reference to public health. Despite numerous attempts to decrease prevalence of human salmonellosis cases, efforts in the United States have largely failed because current regulations focus on Salmonella as a genus, which lacks the nuance necessary to implement serovar- and subtype-specific regulations based on risk. Additionally, comparative transcriptomic analyses can be useful in helping to determine mechanisms underlying differences in host specificity and virulence in NTS serovars. Finally, we used genomic analyses to better understand the evolutionary mechanisms resulting in S. Cerro’s adaptation to cattle. Overall, this work broadens the understanding of the diversity of the genus Salmonella, and emphasizes that this diversity should be properly accounted for when considering policy options to decrease prevalence of human salmonellosis. In order to design risk assessments that properly estimate the public health impact of policy measures that target specific NTS serovars, a better understanding of the mechanisms that cause virulence attenuation and adaptation to a specific host is necessary. The characterization of NTS serovars presented in these studies will allow for better control strategies of Salmonella in food commodities.