Diarrheal disease is a global public health threat. Cases of enteric disease caused by bacterial enteropathogens result in a significant health burden and can lead to antimicrobial resistance patterns that increase and evolve over time and geography, posing serious health challenges for local populations as well as civilian travelers and military personnel deployed to endemic regions. This review describes the prevalence of the most common bacterial agents of diarrheal disease in South America, as well as the distribution patterns of antibiotic resistance and predominant strains that are present in the region. Furthermore, the development of relevant prevention and treatment strategies are described, and United States Naval Medical Research Unit SOUTH disease surveillance and enteric disease research efforts in this regional context are highlighted.