Both evidence-based medicine (EBM) and biological psychiatry aim to improve clinical practice by basing it more firmly on the results of scientific research. In this chapter, however, I show that the two approaches have very different views on what kinds of research will improve practice. This is because EBM is a form of medical empiricism – it focuses solely on whether treatments work, while biological psychiatry is a form of medical rationalism – it seeks to understand the causes that give rise to observed clinical outcomes. I argue that EBM’s empiricism is ultimately shortsighted and that it should integrate some of the rationalist concerns with pathophysiology. I then use this analysis to draw some lessons for research based on the NIMH’s new Research Domain Criteria.