Improved sanitation provides many benefits to human health and well-being and is integral to achieving Sustainable Development Goal Six. However, many nations, including most of sub-Saharan Africa, are not on track to meeting sanitation targets. Recognizing the inherent complexity of environmental health, we used systems thinking to study sanitation sustainability in Uganda. Our study participants, 37 sanitation actors in three rural districts, were engaged in interviews, group model building workshops, and a survey. The resulting model was parametrized and calibrated using publicly available data and data collected through the Uganda Sanitation for Health Activity. Our simulations revealed slippage from improved sanitation in all study districts, a behavior reflected in real interventions. This implies that systemic changes-changes to the rules and relationships in the system-may be required to improve sanitation outcomes in this context. Adding reinforcing feedback targeting households' perceived value of sanitation yielded promising simulation results. We conclude with the following general recommendations for those designing sanitation policies or interventions: (1) conceptualize sanitation systems in terms of reinforcing and balancing feedback, (2) consider using participatory and simulation modeling to build confidence in these conceptual models, and (3) design many experiments (e.g., simulation scenarios) to test and improve understanding.