Case-control studies are an efficient means of investigating the relationship between an exposure and an outcome, and identifying possible predictors of outcome in the patient population being studied. While case-control studies cannot prove causality, they can establish the strength of the association between an exposure and an outcome. Given that a case-control study is conducted retrospectively with available patient data, it is a relatively cost-effective and efficient study design for establishing evidence in support of future prospective studies, or further developing new hypotheses. In a case-control study, one can study multiple exposures in one patient population, which is especially useful when exposure data is difficult to obtain. Case-control studies are feasible with a small sample size and can often be performed relatively quickly. Compared to a cohort study, a case-control study is more effective for proving the association between an exposure and an outcome in rare diseases or in a patient population with a long induction or latent period between the exposure and outcome. Indeed, case-control studies are sometimes the only viable study design for investigating the relationship between an exposure and an outcome. In this chapter, we will review what a case-control study is, when a case-control study is an appropriate choice for study design, and how to avoid common pitfalls associated with case-control studies. We will review three simple, recently published examples of case-control studies in radiation oncology. Using these examples as a template, we will outline the steps involved in approaching case-control study design.