Classical randomized controlled trials are the gold standard in medical evidence because of their high internal validity. However, their necessarily strict design can limit their external validity and the ability to extrapolate these data to real world patients. Therefore, alternatively designed studies may play a complementary role in evaluating the comparative effectiveness of therapies in nonidealized patients in more naturalistic, real world settings. Observational studies have high external validity and can evaluate real world outcomes. Their strength lies in hypothesis generation and testing and in identifying areas in which further clinical trials may be required. Pragmatic trials are designed to maximize applicability of trial results to usual care settings by relying on clinically important outcomes and enrolling a wide range of participants. A combination of these approaches is preferable and necessary.