A hallmark of neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases, and stroke is a malfunction of mitochondria including cytochrome c oxidase (COX), the terminal enzyme complex of the respiratory chain. COX is ascribed a key role based on mainly two regulatory mechanisms. These are the expression of isoforms and the binding of specific allosteric factors to nucleus--encoded subunits. These characteristics represent a unique feature of COX compared with the other respiratory chain complexes. Additional regulatory mechanisms, such as posttranslational modification, substrate availability, and allosteric feedback inhibition by products of the COX reaction, control the enzyme activity in a complex way. In many tissues and cell types, COX represents the rate-limiting enzyme of the respiratory chain which further emphasizes the impact of the regulation of COX as a central site for regulating energy metabolism and oxidative stress. Two of the best-analyzed regulatory mechanisms of COX to date are the allosteric feedback inhibition of the enzyme by its indirect product ATP and the expression of COX subunit IV isoforms. This ATP feedback inhibition of COX requires the expression of COX isoform IV-1. At high ATP/ADP ratios, ADP is exchanged for ATP at the matrix side of COX IV-1 leading to an inhibition of COX activity, thus enabling COX to sense the energy level and to adjust ATP synthesis to energy demand. However, under hypoxic, toxic, and degenerative conditions, COX isoform IV-2 expression is up-regulated and exchanged for COX IV-1 in the enzyme complex. This COX IV isoform switch causes an abolition of the allosteric ATP feedback inhibition of COX and consequently the loss of sensing the energy level. Thus, COX activity is increased leading to higher levels of ATP in neural cells independently of the cellular energy level. Concomitantly, ROS production is increased. Thus, under pathological conditions, neural cells are provided with ATP to meet the energy demand, but at the expense of elevated oxidative stress. This mechanism explains the functional relevance of COX subunit IV isoform expression for cellular energy sensing, ATP production, and oxidative stress levels. This, in turn, affects neural cell function, signaling, and -survival. Thus, COX is a crucial factor in etiology, progression, and prevalence of numerous human neurodegenerative diseases and represents an important target for developing diagnostic and therapeutic tools against those diseases.