Understanding the historical aspects of medical development is crucial as it allows researchers to build on previous knowledge, appreciate the contextual influences of past work, recognize paradigm shifts, and learn from ethical considerations. Over centuries, many pivotal discoveries have shaped our present understanding of the blood–brain and blood–cerebrospinal fluid barriers. Ancient as well as modern scientists have performed a great variety of anatomical and physiological experiments reflecting persistent curiosity and critical discourse. These seminal works led to the first descriptions of relevant brain structures such as meninges, ventricles, choroid plexuses or cerebrospinal fluid, and paved the way for evolving theories of cerebrospinal fluid production and flow. Furthermore, the ideas of blood–brain compartment separation, the elaboration of a barrier-shielded central nervous system, and models of the brain’s integration in blood and lymphatic circulations developed. Consequently, perception of blood–brain interfaces gradually shifted from static barriers to dynamic, responsive borders. This chapter sheds light on the transformative scientific debates and discoveries that led to current knowledge, illustrating the importance of iterative learning and critical reassessment in scientific pursuits.