Objectives: Over half of the world's population (4 billion people) experience severe water scarcity at least one month per year, while half a billion people experience severe water scarcity throughout the year. Despite progress from national and global interventions, a staggering proportion of the Global South remains water insecure. Rapid urban growth and associated demographic changes, climate change, and governance failure have also fostered the growth and expansion of urban informal settlements and slums where widespread poverty and environmental hazards exacerbate the impact of water insecurity on health. This article reflects on the interactions between water insecurity and urban poverty in the Global South across four categories of health outcomes: gastrointestinal diseases, mosquito-borne diseases, injuries, and mental illness. These examples highlight the mechanisms through which urban poverty exacerbates the adverse health effects of water insecurity.Methods: The four selected health outcomes were chosen a priori to represent two communicable conditions with well-developed literatures, and two noncommunicable conditions with newer literatures that have emerged over the last decade. We conducted a narrative literature review of scholarly and gray literature appearing between January 2000 and April 2019 using several online scholarly databases. Results: Gastrointestinal diseases, mosquito-borne diseases, injuries, and mental illness all exemplified the relationship between water insecurity and urban poverty through human biological pathways. For each of the four health categories, we identified frontiers for human biology research contributions to the water-poverty-health nexus. Conclusions: We discuss our findings in the context of three crosscutting themes that merit innovative research approaches: stressor interactions and trade-offs, exposure thresholds, and intervention efficacy. We reiterate that the global burden of disease associated with water insecurity cannot be addressed in isolation from efforts to alleviate extreme poverty.