A new federal agency-approved last month by the United States Congress-is already off to a rocky start. The Advanced Research Projects Agency for Health (ARPA-H), proposed by President Biden in 2021, aims to tackle the most intractable biomedical problems by funding innovative, high-risk, high-reward research and swiftly turning discoveries into treatments and cures. But Congress gave the agency a much smaller budget than sought by the administration-$ 1 billion over 3 years, a fraction of the $6.5 billion requested. And as happens whenever there is new money and a new federal agency, a political scrum has erupted over who should control ARPA-H. It is now expected to answer to both the National Institutes of Health (NIH) and the Department of Health and Human Services (HHS). If it is to deliver on its mission, ARPA-H needs to be an autonomous entity that approaches biomedical research in a way never done before by the federal government. The stakes are high: If ARPA-H fails to produce new clinical advances relatively quickly, it will erode trust in US science. It's time for clear thinking and action about what it will take to make ARPA-H successful.