Adrenomedullin (AM) is a unique bioactive molecule, originally isolated from human pheochromocytoma by monitoring cyclic adenosine monophosphate (cAMP) elevation in platelets. PreproAM mRNA and its translated peptide have been recognized to be widely distributed in the organs of rodents and humans, including heart and vasculature. AM exhibits vasorelaxant activity working on vascular endothelial cells and smooth muscle cells. In addition, AM modulates left ventricular contractility and remodeling in the hypertrophied/failing heart, and alters the structural integrity of the vascular wall. Furthermore, immunocompetent cells, such as macrophage-, and mast cell-derived AM might contribute to the pathogenesis of cardiovascular disorders. Most biological actions mediate cAMP-protein kinase A signaling, whereas cAMP-independent pathways, such as the nitric oxide/soluble guanylate cyclase/cGMP pathway, modulated in molecules/signaling associated with anti-oxidative stress and anti-apoptotic pathways, are also reported. Overall, the actions of AM are assumed to be beneficial against vasoconstrictive factors activated in the diseased heart and vascular wall, whereas some reports imply that the biological activity of AM might be dependent on circumstances. Specifically, inotrophic action, activation of adhesion molecules and smooth muscle proliferation by AM has been debated. In this review, we will present the recent advances in AM research, and discuss the controversy of AM actions in cardiac and vascular tissues.