“Primum non nocere”, or “first, do no harm”, is one of the central ethical principles taught to medical students, and one that scientists and policy makers alike should embrace. In this context, to do no harm, we argue that a systems-wide, holistic approach to N and P control is essential. When develop- ing nutrient criteria for a given river or estuary, it is imperative for policy makers to remember that actions in one watershed will affect a neighboring or downstream ecosystem.