The United States is in the midst of a multifaceted public health crisis, marked by increasing midlife mortality rates among nearly all racial and ethnic groups. The burden of this crisis has fallen most heavily among vulnerable populations, particularly individuals with lower levels of income and education. Patterns of rising mortality—which vary across time, space, and causes of death—suggest a complex set of underlying causes, many of which may have been operative for decades. Our understanding of its fundamental drivers remains incomplete. While there are several broad themes that may link the experiences of different areas of the country and demographic groups, the circumstances leading to worsening population health within any given demographic group, place, or time—and the interventions needed to address these trends—are likely to be unique. Consequently, researchers and policy makers will need to think creatively and iteratively about the root causes of worsening population health, adopting both national and local perspectives.