Bold new approaches are urgently needed to overcome global health challenges. The proposed Advanced Research Projects Agency for Health (ARPA-H) is intended to provide rapid health breakthroughs. While new technologies for earlier disease detection and more effective treatment are critical, we urge equal attention be given to the wider (physical, emotional, social, political, and economic) environmental ecosystems driving the non-communicable disease (NCD) crisis in the first place. This requires an integrated, cross-sectoral vision that spans the interwoven connections affecting health across the scales of people, places, and planet. This wider "exposome" perspective considers biopsychosocial factors that promote resilience and reduce vulnerabilities of individuals and communities over time-the many variables driving health disparities. Since life course health is strongly determined by early life environments, early interventions should be prioritized as a matter of effectiveness and social justice. Here, we explore the origins of the Advanced Research Project Agency and point to its potential to build integrated solutions, with wisdom and ethical value systems as a compass. Since the planned ARPA-H is anticipated to spawn international collaborations, the imagined concept is of relevance to a broad audience of researchers. With appropriate input, the quest for health equity through personalized, precision medicine while deconstructing unacceptable structural inequities may be accelerated.