Connexins are an ubiquitous family of proteins that form exameric transmembrane channels (connexons) and intercellular gap junction channels. GJ are important for propagation of the electrical impulse, and allow (patho)physiolocally intercellular chemical communication in many tissues. GJs connecting adjacent cardiomyocytes are formed by Cx43 and have been shown to allow cell-to-cell spreading of necrosis during reperfusion.. During the last years, evidence has been accumulated indicating that Cx43 may modulate cell survival or death after different stimuli by GJ-independent mechanisms. We have recently described that Cx43 is present in the inner mitochondrial membrane of cardiomyocyte and that this localization of Cx43 is important for preconditioning protection. Detailed analysis of the molecular interactions and functions of mitochondrial Cx43 is complicated by the lack of adequate pharmacological tools to modulate its function, and because Cx43(-/-) mice are not viable. Recent work in our laboratory in different models, including transfected HL1 cardiomyocytes and genetically modified animals in which Cx43 is completely replaced by a different connexin isoform normally not expressed in myocardium (Cx32KI (+/+), indicates that Cx43 forms connexons in mitochondrial membranes (corsslinking, and fluorescent dye permeability studies), modulates changes in mitochondrial volume in response to different stimuli, and influences mitochondrial respiration. Thus, available data suggests that the localization of Cx43 at the inner mitochondrial membrane of cardiomyocytes has important (patho)physiological implications. Further research will be necessary to fully elucidate the molecular mechanisms involved, the relevance in heart and other organs, and the potential interest of mitochondrial Cx43 as a therapeutic target.