CYP2D6, one of the major cytochrome P450 isoforms present in the human brain, is associated with the incidence and prevalence of central nervous system (CNS) diseases. Human CYP2D6 and rat CYP2D are involved in the metabolism of various neurotransmitters and neurosteroids. Brain CYP2D can be regulated by endogenous steroids, including sex hormones. The alteration of CYP2D-mediated metabolism induced by endogenous steroids may cause changes in sensitivity to environmental and industrial toxins and carcinogens as well as physiological and pathophysiological processes controlled by biologically active compounds. This review summarizes the current knowledge regarding the distribution, endogenous substrates, and regulation of brain CYP2D.