The science of mathematical modeling aims to describe and evaluate complex phenomena. In epidemiology, modeling allows scientists to simulate the consequences of various intervention and prevention scenarios. In biology, modeling allows one to describe and simulate complex neurophysiologic processes. Similar modeling techniques apply to both scenarios. At the 2006 College on Problems of Drug Dependence (CPDD) workshop, we presented four types of models: traditional epidemiologic, traditional neurobiological/behavioral, knowledge repository epidemiologic, and knowledge repository neurological/behavioral. We discussed commonality and differences in the approaches, interpretations, utility, and limitations. The authors believe that both traditional and knowledge repository models can be very useful in complementary ways to the general scientific community studying substance abuse.