The proposal aims to address Salmonella’s outbreak that resulted in recalls of onions and products containing onions in the U.S and Canada during early May 2020. The FDA Food Safety Modernization Act established science-based minimum standards for the safe growing, harvesting, packing, and holding of vegetables for human consumption, which are subjective and vary as per crop, pathogen, and production practices. Although the incidence of Salmonella in the onion supply chain was unforeseen, the outbreak certainly warrants a comprehensive investigation and designing a cautious long-term approach to avoid or effectively eliminate such contaminations in the future. Despite the potential risk of similar outbreaks, currently, we do not have a strategic plan to prevent Salmonella contamination in onions due to two bottlenecks: 1) lack of knowledge about the mode of colonization and internalization of Salmonella in onions, and 2) limited understanding of the determinants that would impact the onion specific production practices for ensuring safe produce. The objectives of this 2-year project are: (1) To understand the impact of transcriptomic and metabolomic factors on Salmonella colonization in onion varieties, (2) To identify and evaluate the impact of pre-and post-harvest determinants involved in onion production practices on Salmonella contamination, and (3) To characterize the establishment and internalization of Salmonella in onion. A parallel workflow will be established to meet these three objectives, where onion specific component responses induced due to Salmonella colonization will be evaluated using transcriptomic and metabolomic analyses (Objective 1), along with the simultaneous evaluation of the Salmonella attachment and allocation on onion structures (Objective 3). To better understand the role of pre-and post-harvest bulb onion production practices on the susceptibility to Salmonella contamination, a multifactorial field-study will evaluate the role of bulb nutrient and quality traits defined by the genotype, environment, and management practices. Through the onion supply chain interventions, samplings will also be carried out at the onion production sites, packing sheds, and storage houses to monitor the conduciveness of the environment for Salmonella establishment. This study will identify differential transcriptomic and metabolic responses to identify molecular/metabolic markers and establish strategies for breeding Salmonella-safe onion varieties. An in-depth study of Salmonella internalization on onion bulb sheath and its stability would allow other researchers to engage in developing technologies that would eliminate or irradiate possibilities of future outbreaks in onion. Further, by developing a roadmap for safe production practices, it will be possible to model Salmonella’s presence in the onion supply chain based on production practices, seasonal variation, and varieties and minimize the risk of pre/post-harvest contamination in onion fields.