Chromogranin A (CgA), a major component of the chromaffin granules, is co-stored and co-released with catecholamines. It is also expressed in extra-adrenal sites, including the heart. In the rat, CgA localizes in atrial myoendocrine cells, associated with Atrial Natriuretic Peptide (ANP), and in the conduction system. In the human heart it is present in the ventricular myocardium, co-localized with B-type NP (BNP). CgA is the precursor of several biologically active peptides generated by proteolytic processing also in the heart. Two of them, vasostatin-1 (VS-1) and catestatin (Cst), inhibit cardiac contraction and relaxation, counter-regulate beta-adrenergic and endothelinergic stimulation, and protect the heart against ischemia/reperfusion damages. Recently, clinical studies have suggested CgA to be involved also in cardiovascular pathologies. High plasma CgA levels were found in hypertension, chronic and acute heart failure, myocardial infarction, decompensated and hypertrophic heart, and acute coronary syndromes. These alterations correlate with those of conventional cardiovascular biomarkers, such as NP and endothelin-1 (ET-1), and have prognostic relevance, being indicative of both severity of the disease and mortality. Accordingly, the current knowledge indicates CgA as a multifaceted peptide in cardiovascular homeostasis. Whether the influence elicited by the protein on both normal and failing heart is beneficial and/or detrimental, as well as its implication in the cardiac neuroendocrine scenario is under intense investigation. This review will focus on: i) the involvement of CgA and its derived peptides in the mechanisms which sustain cardiac function and compensation, ii) CgA clinical relevance, and iii) its putative value as a clinical biomarker.