The blood-brain barrier (BBB) is a dynamic physical and biological barrier between blood circulation and the central nervous system (CNS). This unique feature of the BBB lies in the structure of the neurovascular unit and its cerebral micro-vascular endothelial cells. The BBB restricts the passage of blood-borne drugs, neurotoxic substances and peripheral immune cells from entering the brain, while selectively facilitating the transport of nutrients across the BBB into the brain. Thus, the integrity and proper function of the BBB is crucial to homeostasis and physiological function of the CNS. A number of transport and carrier systems are expressed and polarized on the luminal or abluminal surface of the BBB to realize these discrete functions. Among these systems, ABC transporters play a critical role in keeping drugs and neurotoxic substances from entering the brain and in transporting toxic metabolites out of the brain. A number of studies have demonstrated that ABCB1 and ABCG2 are critical to drug efflux at the BBB and that ABCC1 is essential for the blood-cerebral spinal fluid (CSF) barrier. The presence of these efflux ABC transporters also creates a major obstacle for drug delivery into the brain. We have comprehensively reviewed the literature on ABC transporters and drug efflux at the BBB. Understanding the molecular mechanisms of these transporters is important in the development of new drugs and new strategies for drug delivery into the brain.