Emerging public health challenges of Shiga toxin (stx)–producing Escherichia coli (STEC) include the occurrence of more frequent or severe disease and risk factors shifts associated with changes, often interconnected, in the pathogen, the population, and the environment. In 3 outbreaks with heightened severity attributed to enhanced pathogen virulence, including the acquisition of an stx2 phage in 1 outbreak, population and environmental factors likely contributed significantly to disease outcomes. Evolving population risk factors that are associated with more severe disease include consumption of fresh produce, contact with STEC-contaminated environments, demographics, socioeconomic status, and immunity. Risks of increasing STEC environmental pollution are related to continued intensification of agriculture and super-shedder cattle. Mitigation strategies include surveillance and research on emerging STEC, development of effective communications and public education strategies, and improved policies and interventions to mitigate risks, including those related to the contamination of produce and the environment, using a “One Health” approach.