Drug epidemics have enormous individual and societal costs that often persist years after the epidemic has declined. Drug use and addiction produce mental and physical health problems, as well as broad societal challenges such as loss of child custody, potential overdose death, crime, and incarceration. Drug epidemics have features of infectious diseases (e.g., contagion-like spread of use initiation) and chronic diseases (e.g., long-term changes in neurobiology). Understanding and responding to these epidemics requires systems approach that considers multiple connected and interacting components and outcomes. The chapter emphasizes adaptive connectivity between brain neurobiology, behavioral economics, environmental, cultural, and legal factors that impact the course of drug epidemics. The authors illustrate how agent-based models can simultaneously address and capture this interconnectivity. They provide examples of model-based policy evaluations and discuss challenges that modeling drug epidemics is facing. Despite numerous challenges, this area of population health research is very promising and fast developing