Over the last 50 years, increasing evidence has documented the ability of cardiac non-neuronal cells to synthesize and release catecholamines (CAs) and the vasorelaxant natriuretic peptides (NPs), which both regulate cardiovascular homeostasis in health and disease. This knowledge has firmly established the concept of the heart as an endocrine organ. The contents of this frame have been richly expanded by the identification of an increasing number of intracardiac endocrine modulators, including Chromogranin-A (CgA) and its derived peptides. In the rat heart, CgA is co-stored and co-released with Atrial NP (ANP) in non-adrenergic myoendocrine atrial cells as well as in atrial and ventricular Purkinje fibres. In the ventricular myocardium of the human hypertrophic and dilated heart, CgA colocalizes with B-type NP (BNP). CgA is the precursor of biologically active peptides produced by proteolytic cleavage. One of them, the human recombinant 1-76 CgA-derived vasostatin-1 (VS-1), is an inhibitor of cardiac contraction and relaxation, a non-competitive counter-regulator of β-adrenergic stimulation and a protecting agent in ischemic preconditioning. Therefore, it may function as a cardiocirculatory homeostatic stabilizer, particularly in the presence of intense adrenergic stimuli, e. g. under stress responses. Since in patients with chronic heart failure circulating CgA levels increase up to 10-20 nM, depending on the severity of the disease and are independent prognostic indicators of mortality, knowledge on the physio-pathological significance of locally produced and/or circulating CgA-derived peptides, as attemped in this synopsis, may pave the way for clinically-oriented cardiovascular applications.