Two seemingly-associated demographic trends have generated considerable interest: income stagnation and rising premature mortality from suicides, drug poisoning, and alcoholic liver disease among U.S. white non-Hispanics with low education. Economists interpret these population-level trends to indicate that despair, induced by financial stressors, is a shared pathway to these causes of death. Although we now have the catchy term “deaths of despair” (DoD), we have yet to study its central empirical claim: that conceptually defined and empirically assessed “despair” is indeed a common pathway to several causes of death. At the level of the person, despair comprises cognitive, emotional, behavioral, and biological domains. Despair can also permeate social relationships, networks, institutions, and communities. Extant longitudinal datasets feature repeated measures of despair—before, during, and after the Great Recession—offering resources to test the role of economic decline-induced despair in premature morbidity/mortality. Such tests must also focus on protective factors that could shield individuals. DoD is more than a phrase; it is a hypothesis that deserves conceptual mapping and empirical study with longitudinal, multi-level data.