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.