The theory of syndemics has received increasing attention in clinical medicine since the onset of the COVID-19 pandemic, due to the synergistic interactions of the disease with pre-existing political, structural, social and health conditions. In simple terms, syndemics are synergistically interacting epidemics that occur in a particular context with shared drivers. When policymakers ask why some communities have higher death rates from COVID-19 compared with other communities, those working from a syndemics framework argue that multiple factors synergistically work in tandem, and populations with the highest morbidity and mortality experience the greatest impact of these interactions. In this Perspective, we use specific case examples to illustrate these concepts. We discuss the emergence of syndemics, how epidemics interact, and what scientists, clinicians and policymakers can do with this information.