Understanding when it is the appropriate time to stop administering the drugs in a chemotherapy-centered treatment program such as onchocerciasis remains a challenge due to cost, imperfect testing procedures, and a lack of long-term experience. Different approaches for assessing when a program can begin the extensive stop-treatment surveys have been recommended, and tested, with varying results. We describe here a practical approach that is based on information on both transmission as well as infection. This new protocol first defines operational transmission zones (OTZs) based on vector breeding sites followed by an epidemiological assessment of the resident populations adjacent to these breeding sites. Basing decisions to stop MDA treatment based on breeding site locations (i.e., transmission zones) rather than on political administrative units, is a practical, cost-effective approach. Importantly, this biology-based approach is more closely related to the actual state of onchocerciasis transmission.