The HIV epidemic has challenged health systems around the world, including those in resource-rich countries. In Harlem, a disenfranchised community in New York City, poverty, mistrust of health care providers, and a frail health care system ill equipped to handle a chronic disease with profound psychosocial elements challenged the ability to mount an effective response to HIV. A step-by-step effort, initially conceptualized as an emergency response, was followed by a systematic approach to strengthen the health system and shape it to address the unique characteristics of the disease and the needs of the community. Lessons learned from this effort have been applied to other health threats in the community and could inform the global response to HIV.