In this review, we highlight recent findings about the role of some mitochondrial proteins in neurological diseases. Studies in mice gene-deleted for Omi/HtrA2 and AIF showed the involvement of these mitochondrial proteins in selective cell degeneration in the spinal cord and brain. In humans, mutations in the mitochondrial protein, Paraplegin, cause an autosomal form of hereditary spastic paraplegia with an enhanced sensitivity to oxidative stress. Reactive oxygen species and decreased respiratory chain activity in mitochondria also contribute to common neurological diseases. The mitochondrial uncoupling protein, Ucp-2, was found to be neuroprotective in experimental stroke and brain trauma. Recent proteomic and profiling studies have revealed the existence of additional mitochondrial proteins with unknown functions. The elucidation of the physiological functions of mitochondrial proteins may lead to new insights into the role of these organelles in cell degeneration and to identification of novel drug targets for the prevention and treatment of different diseases.