The blood-brain barrier is a natural diffusion barrier, which expresses active carriers extruding drugs on their way to the brain back into the blood against concentration gradients. Whereas these so-called adenosine triphosphate-binding cassette (ABC) transporters prevent the brain entry of toxic compounds under physiological conditions, they complicate pharmacotherapies in neurological disease. Recent observations in animal models of ischemic stroke, drug-resistant epilepsy, and brain cancer showed that the prototype of ABC transporters, ABCB1, is upregulated on brain injury, deactivation of this carrier considerably enhancing the accumulation of neuroprotective, antiepileptic, and chemotherapeutic compounds. These studies provide the proof of concept that the efficacy of brain-targeting drugs may significantly be improved when drug efflux is blocked. Under clinical conditions, efforts currently are made to enhance drug accumulation by selecting new compounds that do not bind to efflux carriers or deactivating ABC transporters by targeted downregulation or pharmacological inhibition. We predict that strategies aiming at circumventing drug efflux may greatly facilitate progress in neurological therapies.