The drug delivery across blood brain barrier (BBB) is hampered by the presence of ATP binding cassette transporters, such as Pglycoprotein (Pgp), which effluxes back into the bloodstream several drugs, e.g. anticancer agents like doxorubicin. Pgp is induced by the transcription factor hypoxia-inducible factor-1α (HIF-1α). By using brain microvascular endothelial cells of murine and human origin cultured in normoxia and hypoxia, we observed that - despite species-specific differences, due to the differential basal activity of HIF-1α the delivery of Pgp substrates is severely reduced in hypoxic BBB cells. Besides increasing the expression of Pgp, however, HIF-1α also increased the expression of low density lipoprotein receptor (LDLR), by activating the sterol regulatory element binding protein-2. The amount of LDLR was further enhanced by simvastatin in hypoxia. Combining simvastatin plus a “LDL-masked” liposomal doxorubicin is an effective strategy to improve the drug delivery across hypoxic BBB cells.