Molecular imaging is a rapidly evolving discipline with the goal of developing tools to display and quantify molecular and cellular targets in vivo. The heart of this field is based on the rational design and screening of targeted and activatable imaging reporter agents to sense fundamental processes of biology. Parallel advances in small animal imaging systems and in agent synthesis have allowed molecular imaging applications to extend into the in vivo arena. These advances have permitted, for example, in vivo sensing of inflammation, apoptosis, cell trafficking, and gene expression. In this review, we first review core principles of molecular imaging with an emphasis on smart, activatable agent technology. We then discuss applications of state-of-the-art molecular probes to interrogate important aspects of cardiovascular biology, with a focus on atherosclerosis, thrombosis, and heart failure. In the ensuing years, we anticipate that fundamental aspects of cardiovascular biology will be detectable in vivo, and that promising molecular imaging agents will be translated into the clinical arena to guide diagnosis and therapy of human cardiovascular illness.