The prevailing view of mitochondria as bioenergetic facilitators has been recently extended by the observation that these organelles play critical roles in many cellular events. Using embryonic stem (ES) and induced pluripotential stem (iPS) cells as in vitro models, we are investigating the participation of mitochondria in the maintenance of stem cell pluripotency and the capacity for differentiation. In particular we are examining the role of mitochondrial-generated reactive oxygen species (ROS) during differentiation to the cardiovascular lineage. We are exploring the possibility that ROS have the capacity to regulate microRNA (miRNA) expression during this progression, and we have recently identified several miRNAs that are differentially expressed upon ROS depletion. In addition, we are devising protocols for the directed differentiation of human iPS cells to cardiac progenitor populations, in the hope that these cells might have therapeutic potential. We are also examining the possibility that stem cells derived from patients with congenital defects might provide valuable models of cardiovascular disease. Our long-term interest in the citric acid cycle has led us to examine the role of mitochondrial dysfunction during heart failure and we are currently creating a knockout mouse model to test our hypothesis that mitochondrial metabolites play important roles during angiogenesis and remodeling after myocardial infarction. We expect that together these approaches will contribute to the understanding of mitochondrial participation during cardiovascular development and disease.