The U.S. Department of Health and Human Services (HHS) profoundly affects the lives of all Americans. Its agencies and programs protect against domestic and global health threats, assure the safety of food and drugs, advance the science of preventing and conquering disease, provide safeguards for America’s vulnerable populations, and improve health for everyone. However, the department faces serious and complex obstacles, chief among them rising health care costs and a broadening range of health challenges. Over time, additional responsibilities have been layered onto the department, and other responsibilities removed, often without corresponding shifts in positions, procedures, structures, and resources. At the request of the U.S. House of Representatives Committee on Oversight and Government Reform, HHS in the 21st Century assesses whether HHS is ‘ideally organized’ to meet the enduring and emerging health challenges facing our nation. The committee identifies many factors that affect the department’s ability to address its range of responsibilities, including divergence in the missions and goals of the department’s agencies, limited flexibility in spending, impending workforce shortages, difficulty in retaining skilled professionals, and challenges in effectively partnering with the private sector.