Brain imaging is simply a tool, a technique. It does not provide scientifically privileged data, it alone cannot generate valid findings, and it cannot substitute for good study design. In most studies designs, imaging provides only correlational data and cannot inform us about the mechanisms of pathogenesis or treatment response. The next generation of imaging studies will increasingly yoke brain imaging to studies with designs that can provide greater causal inference for brain-based disease mechanisms and treatment responses, such as epidemiologicalstudies, longitudinal studies, high risk samples, and randomized clinical trials. Examples of each and their relevance to understanding disease mechanisms and informing real-world clinical care will be provided.