Fine tuning of integrated mitochondrial functions is essential in neurons and rationalizes why mitochondrial dysfunction plays an important pathogenic role in neurodegeneration. Mitochondria can contribute to neuronal cell death and axonal dysfunction through a plethora of mechanisms, including low ATP levels, increased reactive oxygen species, defective calcium regulation, and impairment of dynamics and transport. Recently, mitochondrial proteases in the inner mitochondrial membrane have emerged as culprits in several human neurodegenerative diseases. Mitochondrial proteases degrade misfolded and non-assembled polypeptides, thus performing quality control surveillance in the organelle. Moreover, they regulate the activity of specific substrates by mediating essential processing steps. Mitochondrial proteases may be directly involved in neurodegenerative diseases, as recently shown for the m-AAA protease, or may regulate crucial mitochondrial molecules, such as OPA1, which in turn is implicated in human disease. The mitochondrial proteases HTRA2 and PARL increase the susceptibility of neurons to apoptotic cell death. Here we review our current knowledge on how disturbances of the mitochondrial proteolytic system affect neuronal maintenance and axonal function.