Comparative effectiveness research generates evidence from observational studies and randomized controlled trials. For many clinical questions, the observational study is an efficient design. Sometimes inherent biases in observational studies yield false results that require refutation by a randomized controlled trial. An illustrative example occurred with hormone replacement therapy in post-menopausal women. Numerous observational studies showed benefits of estrogen plus progesterone to prevent coronary heart disease and other adverse outcomes. A subsequent large, randomized controlled trial demonstrated that the harms of hormone replacement therapy exceeded the benefits. Randomized controlled trials play an important role in comparative effectiveness research. To understand this role, it is necessary to have knowledge about bias, ethics, efficacy, and effectiveness. The current chapter explains the benefits of randomization to reduce bias in the context of controlled clinical trials. There is also an explanation of the ethical principles that inform the design of trials. Finally, the chapter differentiates efficacy from effectiveness and explores trial design characteristics related to the differences.