The Global Enteric Multicentre Study (GEMS) was a case-control study that identified Shigella as a leading causes of moderate-to-severe diarrhoea in children under the age of 5 years old in sub-Saharan Africa and Asia, yet Shigella is increasingly resistant to antimicrobials, and there is no licensed vaccine. Here, we performed large-scale analysis of approximately 1500 Shigella from GEMS to determine the genomic and genetic diversity among this relevant, systematically obtained isolate collection to draw out implications for management of the disease with antimicrobials as well as prevention through vaccination. We find differences among the diversity between Shigella species and collection sites, including variation in the epitope region of protein antigen vaccine targets and serotype switching events that will affect glycoconjugate vaccination approaches. We also identify significant differences between species and site with regard to the development of antimicrobial resistance and, finally, in conducting a pathogen genome-wide-association-study, we identify pathogen genetic factors that contribute to the elaboration of shigellosis. Thus, whole genome sequence analysis of this representative dataset has provided a new lens through which to view the diversity of these pathogens in those populations most vulnerable to severe disease and highlighted several significant hurdles we may face in continued management of the disease through antimicrobials and in implementing future vaccination programs