The last several decades have seen remarkable advances in the clinical neurosciences, with some of the most remarkable achievements related to neuroimaging. Given the current depth of knowledge about the brain, it is difficult to appreciate that barely 300 years ago this organ was almost a complete mystery, particularly as to its function. While the brain has been recognized as an “organ” since antiquity, no functional role was ascribed to it until the early 1600s, when Descartes placed the “soul” in one of its small parts, the pineal gland.[1] Prior to this intriguing, but erroneous, concept, much more functional importance had been attributed to the fluid in the ventricles than to the brain itself. Descartes’ non-scientific attribution was, fortunately, quickly followed by the much more rigorous description of the structure of the brain by Thomas Willis in 1664.[2] While Willis’ application of the scientific method to the brain was seminal, the primitive scientific tools available at the time limited his direct observations to anatomy, and gross anatomy at that, which in and of itself does not convey function. Despite little direct evidence, Willis began to argue that mental functions reside in the brain, as do certain diseases such as epilepsy. The scientific tools necessary to prove his assertions by actual observation of physiology, molecular biology, and other “functional” aspects of the brain were still several centuries away.