In recent years there has been increasing focus on the role of the drug transporter P-glycoprotein (P-gp) with regard to drug penetration into the brain. Studies using mice devoid of functional P-gp have revealed that P-gp at the blood-brain barrier (BBB) can exert a profound effect on the ability of some drugs to enter the brain, e.g. cardiovascular drugs (digoxin, quinidine), opioids (morphine, loperamide, methadone), HIV protease inhibitors, the new generation of antihistamines, and some antidepressants and antipsychotics. Among the latter group, risperidone is strongly influenced having about 10 times higher cerebral concentration in P-gp knock-out mice than in control mice. Taking into account that polytherapy is commonplace in psychiatry, theoretically there is a risk of drug-drug interactions with regard to P-gp at the BBB. Here we review the evidence for a role of P-gp with regard to psychoactive drugs from in vitro studies and experiments in knock-out mice devoid of functional P-gp. Moreover, the evidence for significant drug-drug interactions involving psychotropic drugs in rodents is considered. Clinical observations suggesting a role for P-gp in relation to drug-drug interactions at the BBB are sparse, and a definite conclusion awaits further studies. Also, the possible clinical relevance of P-gp genetic polymorphisms is questionable, and more investigations are needed on this subject.