Adenosine monophosphate-activated protein kinase (AMPK) is a ubiquitously expressed cellular energy sensor in the heart and an essential component of the adaptive response to cardiomyocyte stress. However, its actions extend far beyond its role in energy regulation, and it appears to control many processes in non-myocytes under different pathological conditions. Here we will overview the role of AMPK signaling in the cardiovascular system, focusing on platelets, cardiac fibroblasts, and endothelial cells. We will discuss recent insights into the molecular mechanisms by which AMPK can influence atherothrombosis, adverse post-infarction fibrosis and capillary permeability, all contributing to the deterioration of cardiac function and predisposing to the development of heart failure.