Mitochondrial disorders are increasingly acknowledged as a major category in clinical neurology. In this review we highlight the most recent advances in the field, including the characterization of new disease genes, new physiopathological insights, and the role of mitochondrial dysfunction in neurodegeneration. Substantial progress has been made on the genetic basis and pathogenic mechanisms in disorders associated with altered mitochondrial DNA stability and expression. These defects include a wide spectrum of neurological conditions caused by genetic abnormalities of the mitochondrial replication and translation machineries, and of the metabolic pathways controlling the nucleotide supply to organelles, cells and tissues. Another relevant contribution has been given to the molecular dissection of coenzyme Q deficiency, a clinically heterogeneous, potentially treatable condition, thanks to the biochemical and genetic characterization of the first defects in coenzyme Q biosynthesis. Finally, the genetic determinants controlling the penetrance of mitochondrial disorders, as well as the role of mitochondrial dysfunction in neurodegenerative conditions such as Parkinson's and Huntington's diseases, have been investigated in both patients and animal models. The dual genetic contribution controlling mitochondrial biogenesis, and the intricacy and universality of the metabolic pathways operating in the mitochondrion explain the complexity of what is now known as 'mitochondrial medicine'.