Research on chromaffn cells dates back to 1856 when the venous outflow of chemical substances from the adrenal medulla into the circulation was frst described. The discovery of the chromaffn granules for storage of catecholamines in 1953 was the next major break-through. Soon thereafter the co-storage of catecholamines, ATP and uniquely acidic proteins was established, together making up the isotonic storage complex within elements of the diffuse sympathoadrenal system. The core proteins constitute a family of eight genetically distinct, uniquely acidic proteins, characterized by numerous pairs of basic residues and collectively named granins. A prohormone concept was formulated when the insulin-release inhibiting peptide, pancreastatin, was identifed as the mid sequence of porcine chromogranin A. Subsequently, processing resulted in a range of peptides with antifungal and antibacterial potencies, predominantly from chromogranin A, a few from chromogranin B and one from secretogranin II. A wide range of biological activites has since been documented, notably for the chromogranin A –derived peptides, affecting endothelial stability, myocardial contractility, angiogenesis, cell adhesion and tumor progression. A physiological role for full-length chromogranin A and vasostatin-I as circulating stabilizers of endothelial integrity is now evident, while the high circulating levels of chromogranin A in neuroendocrine tumors and inflammatory diseases remain an unsolved and challenging puzzle for future research.