Randomized controlled trials (RCTs) constitute the gold standard for the generation of evidence-based medicine, but may not always be feasible. Furthermore, randomization alone does not guarantee the utility of the research, as evidenced by thousands of uninformative RCTs documented in the literature. Observational studies, including longitudinal, retrospective, and case-control designs, can contribute to the body of evidence in meaningful ways, provide useful information when an RCT is unethical or not feasible, generate hypotheses for RCTs, or provide preliminary work to better inform design of future RCTs. They can also be used to study rare outcomes, risk factors, and side effects, and to examine whether results from RCTs translate into effective treatment in routine practice. Use of modern statistical techniques, both in the study design and in the analysis stage, can improve the usefulness of the evidence obtained from observational studies.