The brain performs a multitude of astonishing functions, ranging from fundamental processes such as regulating eating and sleeping to more complex phenomena, such as self-consciousness, believed to have evolved particularly in primates. In vertebrates, these functions are partly modulated by well-established wired transmission, known as synaptic transmission. However, this mode of operation has proven insufficient to explain more complex emergent processes. The cerebrospinal fluid (CSF) and interstitial fluid bathe the entire brain, providing access to various cell types not only in the brain but also in the spinal cord. Exploring volume transmission may offer insights into aspects of brain function that cannot be elucidated solely through wired transmission studies. In this chapter, we will delve into various instances of volume transmission in vertebrates, exploring its potential therapeutic applications in humans. Additionally, we will explore the evolutionary implications of volume transmission, providing insights into its development and significance across phyla.