Recently, the hypothalamic 82-aa peptide Nesfatin-1 received notable attention for its anorexigenic and anti-hyperglycemic properties. In mammalian hypothalamus, Nesfatin-1 is expressed, together with the precursor Nucleobindin 2 (NUCB2), in regions controlling water-food intake, body weight, and glucose homeostasis. The peptide is also peripherally expressed, as shown in the rat heart, in which it is present together with NUCB2. In addition to a central modulation of nutrition and energy balance, and of the nervous circuits responsible for blood pressure and heart rate control, Nesfatin-1 also acts peripherally on several districts, including the cardiovascular (CV) system. Accordingly, the peptide is regarded with interest as a multifunctional hormone not only linked to alimentary homeostasis. This review aims to analyze the literature on Nesfatin-1, with focus on its emerging CV activity. Few available studies show that the peptide affects energy metabolism of murine and human cardiomyocytes, by eliciting insulin-like effects. On the ex vivo rat heart, it directly depresses contractility and relaxation via cGMP, PKG and ERK1/2, and limits ischemia/reperfusion (I/R) damage, acting in post-conditioning protection. Nesfatin-1 actions are proposed to involve an unknown G-protein coupled receptor. However, in the rat heart, functional studies, co-immunoprecipitation and local sequence alignment analyses suggest an interaction with the Natriuretic Peptide Receptor-type A (NPR-A). These data open up novel perspectives to clarify not only the biological significance of the peptide, but also its putative biomedical potential in the presence of nutrition-dependent cardiovascular diseases.