In the 15th century, brain illustration began to change from a schematic system that involved scant objective rendering of the brain, to accurate depictions based on anatomical dissections that demanded significant artistic talent. Notable examples of this innovation are the drawings of Leonardo da Vinci (1498–1504), Andreas Vesalius' association with the bottega of Titian to produce the drawings of Vesalius' De humani corporis fabrica (1543), and Christopher Wren's illustrations for Thomas Willis' Cerebri Anatome (1664). These works appeared during the Renaissance and Age of Enlightenment, when advances in brain imaging, or really brain rendering, reflected not only the abilities and dedications of the artists, but also the influences of important cultural and scientific factors. Anatomy and human dissection became popular social phenomena as well as scholarly pursuits, linked with the world of the fine arts. The working philosophy of these artists involved active participation in both anatomical study and illustration, and the belief that their discoveries of the natural world could best be communicated by rendering them in objective form (that is, with realistic perspective). From their studies emerged the beginning of contemporary brain imaging. In this article, the authors examine how the brain began to be imaged in realism within a cultural and scientific milieu that witnessed the emergence of anatomical dissection, the geometry of linear perspective, and the closer confluence of art and science.