Multiple sclerosis (MS) is a progressive inflammatory disease of the central nervous system (CNS) leading to severe neurological deficits. To date, no treatment is available that halts disease progression, but clinical symptoms can be generally improved by therapies involving anti-inflammatory and/or immune modulatory reagents, which may cause off-target effects. Therefore, there remains a high and unmet need for more selective treatment strategies in MS. An early event in MS is a diminished function of the blood-brain barrier (BBB) which consists of specialized brain endothelial cells (BECs) that are supported in their barrier function by surrounding glial cells. Leakage and inflammation of the BECs in MS patients facilitate the massive influx of leukocytes into the brain parenchyma, which in turn induces irreversible demyelination, tissue damage and axonal dysfunction. Identification of ways to restore BBB function and promote its immune quiescence may therefore lead to the development of novel therapeutic regimes that not only specifically reduce leukocyte entry into the central nervous system but also restore the disturbed brain homeostasis. However, the complex network of molecular players that leads to BBB dysfunction in MS is yet to be fully elucidated. Recent discoveries unravelled a critical role for microRNAs (miRNAs) in controlling the function of the barrier endothelium in the brain. Here we will review the current knowledge on the involvement of BBB dysfunction in MS and the central role that miRNAs play in maintaining BBB integrity under inflammatory conditions.