Mathematical modeling is a valuable methodology used to study healthcare epidemiology and antimicrobial stewardship, particularly when more traditional study approaches are infeasible, unethical, costly, or time consuming. We focus on 2 of the most common types of mathematical modeling, namely compartmental modeling and agent-based modeling, which provide important advantages-such as shorter developmental timelines and opportunities for extensive experimentation-over observational and experimental approaches. We summarize these advantages and disadvantages via specific examples and highlight recent advances in the methodology. A checklist is provided to serve as a guideline in the development of mathematical models in healthcare epidemiology and antimicrobial stewardship. Infect Control Hosp Epidemiol 2016;1-7.