Approximately 9.4 million episodes of domestically acquired foodborne illnesses due to known pathogens have been reported to occur in the United States (US) each year. Among foodborne pathogens, nontyphoidal Salmonella (NTS) and Listeria (L.) monocytogenes represent great public health concern: NTS is the leading cause of foodborne illnesses and deaths in the US (responsible for 11% and 28% of the illnesses and deaths, respectively), while L. monocytogenes has a high fatality rate of 16% and mainly targets pregnant women (who can pass it on to their newborns), the elderly, as well as immunocompromised individuals. Despite the high public health significance, current food regulatory policies and control strategies associated with NTS and L. monocytogenes have not been proved successful, marked by the continuous failure (e.g., by the Healthy People 2010 and 2020 initiatives) for achieving the targeted reduction of human salmonellosis cases and the frequent association of L. monocytogenes to both foodborne outbreaks and food recalls. Consequently, a constant improvement of regulatory policies and control strategy for a reduced risk associated with these two pathogens in food supply is of crucial importance. This dissertation details four studies which, from different angles, facilitate the development of NTS and L. monocytogenes regulatory policies and control strategies with improved public health impacts. Specifically, two challenge studies with high or low L. monocytogenes inoculation levels provided practical guidance on assessing efficacy of interventions and experimental data that support both the development and validation of risk assessment models. A modeling framework was then developed to predict risks of regulatory consequences (e.g., recalls) associated with L. monocytogenes, as well as risk reduction due to different interventions. Lastly, a genomics-based framework was developed, which facilitates the identification and characterization of hypo- or hyper-virulent NTS subtypes and their associated genomic signatures. The results of these studies support a few high-level conclusions regarding the overall control of risks associated with NTS and L. monocytogenes in the US food supply. The efficacy of L. monocytogenes interventions varies across different situations and thus should be assessed conditional on factors that at least include inoculum size, storage temperature, strain or serotype diversity, and worst-case scenarios that may confer cross-protection. Regulatory policies simply based on the presence/absence of L. monocytogenes may inadvertently incentivize unbalanced dedication of resources for reducing business risks versus public health risks. To this end, risk assessment models focusing on risks of regulatory consequences (e.g., recalls) should be used to optimize the resource allocation for co-management of different types of risks. Finally, we highlight the need to shift the regulations and control strategies of NTS from serovar-classification-based to quantitative and risk-based approaches for maximizing public health impacts. This proposed new paradigm would benefit from the genomics framework we developed, which has demonstrated merit in identification and characterization of Salmonella subtypes with differential human virulence and the associated genomic signatures across NTS serovars.