Agent-based models (ABMs) have grown in popularity in epidemiologic applications, but the assumptions necessary for valid inference have only partially been articulated. In this issue, Murray et al. (Am J Epidemiol. 2017;186(2):131–142) provided a much-needed analysis of the consequence of some of these assumptions, comparing analysis using an ABM to a similar analysis using the parametric g-formula. In particular, their work focused on the biases that can arise in ABMs that use parameters drawn from distinct populations whose causal structures and baseline outcome risks differ. This demonstration of the quantitative issues that arise in transporting effects between populations has implications not only for ABMs but for all epidemiologic applications, because making use of epidemiologic results requires application beyond a study sample. Broadly, because health arises within complex, dynamic, and hierarchical systems, many research questions cannot be answered statistically without strong assumptions. It will require every tool in our store of methods to properly understand population dynamics if we wish to build an evidence base that is adequate for action. Murray et al.’s results provide insight into these assumptions that epidemiologists can use when selecting a modeling approach.