In a JAMA Special Communication message, Victor Dzau and colleagues, including Shiriki Kumanyika, review the most salient health challenges and opportunities facing the United States, and seek to identify practical priorities and policy initiatives essential to health progress. The authors assess 19 National Academy of Medicine-commissioned white papers, and review publicly available data on health care costs and outcomes. They find that, of the $3.2 trillion spent annually on health care, an estimated 30% is related to waste, inefficiencies, and excessive price. Major health challenges include worsening health disparities, and health and financial burdens of chronic illness and disability. At the same time, the authors identify several action priorities and infrastructure needs. The action priorities include paying for value, empowering people, activating communities, and connecting care. Infrastructure needs cited as foundational to progress include measuring what matters most, modernizing skills, accelerating real-world evidence, and advancing science. The authors conclude that leadership and strategic investment in these priorities will be essential for achieving significant progress.