The need to protect neural tissue from toxins or other substances is as old as neural tissue itself. Early recognition of this need has led to more than a century of investigation of the blood-brain barrier (BBB). Many aspects of this important neuroprotective barrier have now been well established, including its cellular architecture and barrier and transport functions. Unsurprisingly, most research has had a human orientation, using mammalian and other animal models to develop translational research findings. However, cell layers forming a barrier between vascular spaces and neural tissues are found broadly throughout the invertebrates as well as in all vertebrates. Unfortunately, previous scenarios for the evolution of the BBB typically adopt a classic, now discredited ‘scala naturae’ approach, which inaccurately describes a putative evolutionary progression of the mammalian BBB from simple invertebrates to mammals. In fact, BBB-like structures have evolved independently numerous times, complicating simplistic views of the evolution of the BBB as a linear process. Here, we review BBBs in their various forms in both invertebrates and vertebrates, with an emphasis on the function, evolution, and conditional relevance of popular animal models such as the fruit fly and the zebrafish to mammalian BBB research.