In the middle of the last century, Archie Cochrane, one of the founding fathers of evidence-based medicine, argued that understanding healthcare treatments required the consideration of three questions: “Can it work?”, “Does it work?” and “Is it worth it?” Each of these questions addresses a different aspect of the problem and requires different assumptions and different research methodologies. Understanding if a treatment can work establishes proof of principle derived from efficacy studies that control who takes the treatment, how it is administered, and how outcomes are measured. The question “Does it work?” is about effectiveness that is evaluated under conditions of the usual care. Randomized controlled trials, which form the core of efficacy research, are difficult to employ in the evaluation of effectiveness. Even if interventions are shown to be efficacious and effective, people need to decide if accepting the treatment is worth it. Healthcare can be expensive, inconvenient, painful, and sometimes of little value. This introductory chapter reviews the three questions and prepares the reader for the in-depth discussion of these issues in the following 16 chapters.