The accurate regulation of the microenvironment within the nervous system is one of the key features charac-terizing complex organisms. To this end, neural tissue has to be physically separated from circulation, but at the same time, mechanisms must be in place to allow controlled transport of nutrients and macromolecules into and out of the brain. These roles are executed by cells of the blood-brain barrier (BBB) found at the interface of circulation and neural tissue. BBB dysfunction is observed in several neurological diseases in human. Although this can be considered as a consequence of diseases, strong evidence supports the notion that BBB dysfunction can promote the progression of brain disorders. In this review, we compile the recent evidence describing the contribution of the Drosophila BBB to the further understanding of brain disease features in human patients. We discuss the function of the Drosophila BBB during infection and inflammation, drug clearance and addictions, sleep, chronic neurodegenerative disorders and epilepsy. In summary, this evidence suggests that the fruit fly, Drosophila melanogaster, can be successfully employed as a model to disentangle mechanisms underlying human diseases.