The essential trace element selenium, as selenocysteine, is incorporated into antioxidant selenoproteins such as glutathione peroxidases (GPx), thioredoxin reductases (TrxR) and selenoprotein P (Sepp1). Although comparatively low in selenium content, the brain exhibits high priority for selenium supply and retention under conditions of dietary selenium deficiency. Liver-derived Sepp1 is the major transport protein in plasma to supply the brain with selenium, serving as a “survival factor” for neurons in culture. Sepp1 expression has also been detected within the brain. Presumably, astrocytes secrete Sepp1, which is subsequently taken up by neurons via the apolipoprotein E receptor 2 (ApoER2). Knock-out of Sepp1 or ApoER2 as well as neuron-specific ablation of selenoprotein biosynthesis results in neurological dysfunction in mice. Astrocytes, generally less vulnerable to oxidative stress than neurons, are capable of up-regulating the expression of antioxidant selenoproteins upon brain injury. Occurrence of neurological disorders has been reported occasionally in patients with inadequate nutritional selenium supply or a mutation in the gene encoding selenocysteine synthase, one of the enzymes involved in selenoprotein biosynthesis. In three large trials carried out among elderly persons, a low selenium status was associated with faster decline in cognitive functions and poor performance in tests assessing coordination and motor speed. Future research is required to better understand the role of selenium and selenoproteins in brain diseases including hepatic encephalopathy.