The coupling of respiration to ADP phosphorylation in mitochondria represents the coupling of exergonic and endergonic processes. Actually, such a coupling is never complete and results in energy dissipation as heat. Apart from a role in thermogenesis, uncoupling of respiration limits ATP synthesis and allows NADH reoxidation. In the absence of uncoupling mechanisms, a high level of ATP would inhibit respiration and NADH reoxidation. Two types of mechanisms have been proposed to explain the molecular basis of respiration uncoupling. The ﬁrst is based on a decreased eﬃciency of the respiratory chain or ‘‘slippage’’ of respiratory chains; the second one postulates the existence of proton leaks in the mitochondrial inner membrane. Analysis of thermogenic mechanisms in brown adipocytes has established that UCP1 in the inner mitochondrial membrane works as a regulatable proton leak and an uncoupler that stimulates fatty acid oxidation (see below). The recent identiﬁcation of homologues of UCP1 has extended this regulatory mechanism based on the possible mitochondrial proton leaks to virtually all other tissues. Accordingly, this phenomenon of mitochondrial proton leaks represents a widespread strategy for controlling substrate utilization, and energy partitioning through changes in metabolic eﬃciency.