Compelling evidence demonstrates the emerging role of mitochondrial complex I deficiency in the onset and development of cardiovascular diseases (CVDs). In particular, defects in single subunits of mitochondrial complex I have been associated with cardiac hypertrophy, ischemia/reperfusion injury, as well as diabetic complications and stroke in pre-clinical studies. Moreover, data obtained in humans revealed that genes coding for complex I proteins were associated with different CVDs. In this review, we discuss recent experimental studies that underline the contributory role of mitochondrial complex I deficiency in the etiopathogenesis of several CVDs, with a particular focus on those involving loss of function models of mitochondrial complex I. We also discuss human studies and potential therapeutic strategies able to rescue mitochondrial function in CVDs.