Randomized controlled trials (RCT) produce the strongest level of clinical evidence when comparing interventions. RCTs are technically difficult, costly, and require specific considerations including the use of patient- and cluster-level randomization and outcome selection. In this methods paper, we focus on key considerations for RCT methods in healthcare epidemiology and antimicrobial stewardship (HE&AS) research, including the need for cluster randomization, conduct at multiple sites, behavior modification interventions, and difficulty with identifying appropriate outcomes. We review key RCTs in HE&AS with a focus on advantages and disadvantages of methods used. A checklist is provided to aid in the development of RCTs in HE&AS. Infect Control Hosp Epidemiol 2016;37:629-634.