Mitochondria have long been known to play a critical role in maintaining the bioenergetic status of cells under physiological conditions. It was also recognized early in mitochondrial research that the reduction of oxygen to generate the free radical superoxide occurs at various sites in the respiratory chain and was postulated that this could lead to mitochondrial dysfunction in a variety of disease states. Over recent years, this view has broadened substantially with the discovery that reactive oxygen, nitrogen, and lipid species can also modulate physiological cell function through a process known as redox cell signaling. These redox active second messengers are formed through regulated enzymatic pathways, including those in the mitochondrion, and result in the posttranslational modification of mitochondrial proteins and DNA. In some cases, the signaling pathways lead to cytotoxicity. Under physiological conditions, the same mediators at low concentrations activate the cytoprotective signaling pathways that increase cellular antioxidants. Thus, it is critical to understand the mechanisms by which these pathways are distinguished to develop strategies that will lead to the prevention of cardiovascular disease. In this review, we describe recent evidence that supports the hypothesis that mitochondria have an important role in cell signaling, and so contribute to both the adaptation to oxidative stress and the development of vascular diseases. © 2006 American Heart Association, Inc.