The ability of parasites to manipulate host behavior to their advantage has been studied extensively, but the impact of parasite manipulation on the evolution of neural and endocrine mechanisms has remained virtually unexplored. If selection for countermeasures has shaped the evolution of nervous systems, many aspects of neural functioning are likely to remain poorly understood until parasites—the brain’s invisible designers—are included in the picture. This article offers the first systematic discussion of brain evolution in light of parasite manipulation. After reviewing the strategies and mechanisms employed by parasites, the paper presents a taxonomy of host countermeasures with four main categories, namely: restrict access to the brain; increase the costs of manipulation; increase the complexity of signals; and increase robustness. For each category, possible examples of countermeasures are explored, and the likely evolutionary responses by parasites are considered. The article then discusses the metabolic, computational, and ecological constraints that limit the evolution of countermeasures. The final sections offer suggestions for future research and consider some implications for basic neuroscience and psychopharmacology. The paper aims to present a novel perspective on brain evolution, chart a provisional way forward, and stimulate research across the relevant disciplines.