Hypothesis generation is a critical, but challenging, step in a foodborne outbreak investigation. The pathogens that contaminate food have many diverse reservoirs, resulting in seemingly limitless potential vehicles. Identifying a vehicle is particularly challenging for clusters detected through national pathogen-specific surveillance, as cases can be geographically dispersed and lack an obvious epidemiological link. Moreover, state and local health departments may have limited resources to dedicate to cluster and outbreak investigations. These challenges underscore the importance of hypothesis generation during an outbreak investigation. In this review, we present a framework for hypothesis generation focusing on three primary sources of information, typically used in combination: (1) known sources of the pathogen causing illness; (2) person, place, and time characteristics of cases associated with the outbreak (descriptive data); and (3) case exposure assessment. Hypothesis generation can narrow the list of potential food vehicles and focus subsequent epidemiologic, laboratory, environmental, and traceback efforts, ensuring that time and resources are used more efficiently and increasing the likelihood of rapidly and conclusively implicating the contaminated food vehicle.