Many academic medical centers are positioned amidst disadvantaged urban neighborhoods in which healthcare services are underutilized, participation in research studies is low, and need for health improvement is vast. The goal of Temple Health: Block-by-Block (THB3) is to establish a sustainable cohort of Philadelphia residents engaged in individual and community health improvement through health research. Recruitment of a population-based sample from 11 Philadelphia zip codes began in August 2015. The cornerstone of the project is the in-home, biannual assessment of each subject. The first-year goal of 1000 enrolled subjects was met. Greater than 90% of subjects represent minority racial or ethnic groups; average age is 46 years; 65% of subjects have a high school education or less. A high burden of health conditions exists including obesity (54%), smoking (41%), hypertension (44%), and diabetes (17.8%). THB3 provides a research infrastructure to promote community participation in a health improvement initiative from which future translational research, health education and preventive services will emanate. The launch of this cohort study has provided extensive lessons regarding urban community-based research and health promotion initiatives.