Over the past few decades, microglial cells have been regarded as the main executor of inflammation after acute and chronic central nervous system (CNS) disorders, responding rapidly to exogenous stimuli during acute trauma or infections, or signals released by cells undergoing cell death during conditions such as stroke, Alzheimer's disease (AD) and Parkinson's disease (PD). Barriers of the nervous system, and in particular the blood-brain barrier (BBB), play a key role in the normal physiological and cognitive functions of the brain. Being at the interface between the central and peripheral compartment, the BBB is regarded as a sensor of homeostasis, and any disruption within the brain or the systemic compartment triggers BBB dysfunction and neuroinflammation, both contributing to the pathogenesis of cerebrovascular disease. This involves a dynamic response mediated by all components of the neurovascular unit (NVU), and ongoing research suggests that BBB-microglia interaction is critical to dictate the microglial response to NVU injury. The present review aims to give an up-to-date account of the emerging critical role of BBB-microglia interactions during neuroinflammation, and how these could be targeted for the therapeutic treatment of major central inflammatory disease.