Challenges associated with water scarcity and increasing water demand are leading many cities around the globe to consider water reuse as a step towards water sustainability. Recycled water may be used in a spectrum of applications, from irrigation or industrial use to direct potable reuse, and thus presents a challenge to regulators as not all applications require the same level of treatment. We propose that traditional drinking water standards identifying “safe” water quality are insufficient for recycled water and that using the “human exposome” as a framework to guide development of a risk management strategy offers a holistic means by which to base decisions impacting water quality. A successful and comprehensive plan for water reuse must consider 1) health impacts associated with both acute and chronic exposures, 2) all routes of exposure by which individuals may encounter recycled water, and 3) water quality at the true point of use after storage and transport through pipe networks, rather than at the point of treatment. Based on these principles we explore key chemical differences between recycled and traditional potable water, implications for distribution systems with respect to design and operation, occurrence of chronic contaminants, and the presence of emerging and often underappreciated microbial contaminants. The unique nature of recycled water has the potential to provide rapid regrowth conditions for certain microbial contaminants in these systems, which must be considered to achieve safe water quality at the point of use.