With the discovery of novel therapeutic targets within the central nervous system (CNS), there has been a significant effort to synthesize a multitude of drug molecules with increasing potency and selectivity. However, the impact of the blood-brain barrier (BBB) in limiting effective concentrations of drug candidate from reaching the brain parenchyma is often ignored, resulting in a lack of efficacy when administered to animal models or humans. Intercellular drug transport across the BBB is negligible due to the impermeable tight junctions formed by interconnecting endothelial cells. Furthermore, drug permeability via the transcellular route cannot be assumed for all molecules due to the high expression of drug efflux transport proteins, which effectively extrude compounds from the brain endothelial cell back into the cerebral vasculature. In addition to the extensively-studied P-glycoprotein (P-gp, ABCB1), the brain endothelial cells also express multidrug resistance associated proteins (MRP, ABCC) and breast cancer resistance protein (BCRP, ABCG2), amongst other efflux transporters. While more research has focussed on the impact of P-gp and MRP on drug transport across the BBB, the role of ABCG2 in limiting exposure of drug molecules to the CNS is now becoming more clearly understood. The purpose of this review, therefore, is to summarise the findings of the various studies assessing the expression profile of ABCG2 at the BBB, to provide an overview on the current research being undertaken to identify specific ABCG2 inhibitors with therapeutic benefit, and to critically assess the functional role of ABCG2 on drug transport across the BBB.