The mechanisms explaining the imperfect coupling of respiration to ADP phosphorylation in mitochondria are not well understood. In the case of a thermogenic organ such as brown adipose tissue, heat production results from a regulated uncoupling of respiration due to a specific uncoupler present in the inner mitochondrial uncoupling protein, referred to as uncoupling protein (UCP)-1. UCP1 functions as a proton translocator regulated by fatty acids. Two UCP homologues were identified very recently; UCP2 is expressed in most organs, whereas UCP3 expression is restricted to skeletal muscle and brown adipose tissue. Experimental data support the respiration uncoupling activity of UCP2 and UCP3. Physiological and genetic data are in agreement with thermogenic activity of the two proteins, although other physiological data favor a role for UCP2 and UCP3 in lipid handling rather than in energy expenditure. UCP2 and UCP3 may also be involved in inflammation, immune response and fever. Many hormones and certain pharmacological regulators affect expression level of UCP2 and/or UCP3 gene.