As strategies in sustainability permeate modern engineering approaches, opportunities to re-engineer our water and sanitation systems in ways that simultaneously address human and ecological needs become apparent. Yet uncertainties remain regarding the human health safety, ecosystem impacts, social acceptance, and economic efficiency of innovative water and waste management infrastructure. I will introduce two areas of my research conducted to reveal opportunities and address uncertainties within this context. First, I will discuss ecological and economic opportunities for using tertiary treated wastewater to renew urban streams. A case study in Pacifica, California demonstrated that the value of ecosystem services provided by a restored stream augmented with recycled water were greater than the additional costs required for implementation. Yet ecological water reuse remains a small portion of California’s water reuse portfolio, just 7% of the volume recycled in 2009. This is due in part to unquantified environmental risks of ecological water reuse. For example, an emerging understanding of the bioaccumulative nature of perfluoroalkyl acids reveals a potential contribution of these persistent micropollutants to ecological risk in such projects. Second, I will present strategies to reduce human and environmental health risks in the scale-up of waste reuse for a city’s decentralized dry sanitation system. In Durban, South Africa, the local municipality aims to recover nutrients from urine to produce agricultural fertilizers. However, source-separated urine also contains excreted pharmaceuticals and pathogens. By evaluating health hazards of collected urine in Durban and treatment efficacy of urine nutrient recovery processes, my work seeks to increase the safety of human waste reuse.