Mitochondrial uncoupling proteins (UCPs), a subfamily of the mitochondrial transporter family, are related by sequence homology to UCP1. This protein, which is located in the inner mitochondrial membrane, dissipates the proton gradient between the intermembrane space and the mitochondrial matrix to uncouple electron transport from ATP synthesis. UCP1 (thermogenin) was first discovered in brown adipose tissue and is responsible for non-shivering thermogenesis. Expression of mRNA for three other UCP isoforms, UCP2, UCP4, and BMCP1/UCP5, has been found at high levels in brain. However, the physiological function(s) of UCPs in the brain have not been determined, although it has recently been postulated that UCPs regulate free radical flux from mitochondria by physiologically modulating mitochondrial membrane potential. In the CNS, this hypothesis has been studied primarily for UCP2. UCP2 message has been shown to be up-regulated in the CNS by stress signals such as kainate administration or ischemia, and overexpression of UCP2 has been reported to be neuroprotective against oxidative stress in vivo and in vitro, although the exact mechanism has not been fully established. In this review, studies on UCPs in the nervous system will be reviewed, and the potential roles of these intriguing proteins in acute and chronic diseases of the nervous system will be discussed.