Pragmatic randomized clinical trials (PrCTs) help patients, clinicians, payers and health policy decision makers to make decisions by providing real-world evidence about healthcare interventions. Randomization is a major component of PrCTs, which ensures a solid statistical foundation for comparing interventions. Several characteristics set PrCTs apart from traditional randomized clinical trials: minimal inclusion/exclusion criteria leading to a heterogeneous population, usual care setting with fewer scheduled visits, multiple data sources (e.g., clinician-collected, electronic health records, insurance claims, mobile devices), real-world interventions and real-world outcomes. The result is a simpler trial design with increased generalizability, but challenges arise, such as: impact on enrollment, larger sample size (e.g., cluster randomization), smaller treatment effect and higher variability in the heterogeneous population, fewer visits (which may render an interim analysis infeasible and reduce adherence) and bias from open label design. This talk will review key design elements of PrCTs, their challenges and impact on clinical practice.