© 2015 Wolters Kluwer Health. Context: More than 2800 local health departments (LHDs) provide public health services to more than 300 million individuals in the United States. This study focuses on departments serving the most populous districts in the nation, including the members of the Big Cities Health Coalition (BCHC) in 2013. Objective: To systematically gather leadership perspectives on the most pressing issues facing large, urban health departments. In addition, to quantify variation in policy involvement between BCHC LHDs and other LHDs. Design: We used a parallel mixed-methods approach, including interviews with 45 leaders from the BCHC departments, together with secondary data analysis of the National Association of County & City Health Officials' (NACCHO) 2013 Profile data. Participants: Forty-five local health officials, chiefs of policy, and chief science/medical officers from 16 BCHC LHDs. Results: The BCHC departments are more actively involved in policy at the state and federal levels than are other LHDs. All BCHC members participated in at least 1 of the 5 policy areas that NACCHO tracks at the local level, 89% at the state level, and 74% at the federal level. Comparatively, overall 81% of all LHDs participated in any of the 5 areas at the local level, 57% at the state level, and 15% at the federal level. The BCHC leaders identified barriers they face in their work, including insufficient funding, political challenges, bureaucracy, lack of understanding of issues by key decision makers, and workforce competency. Conclusions: As more people in the United States are living in metropolitan areas, large, urban health departments are playing increasingly important roles in protecting and promoting public health. The BCHC LHDs are active in policy change to improve health, but are limited by insufficient funding, governmental bureaucracy, and workforce development challenges.