Natriuretic peptides play a critical role in coordination of fluid/electrolyte balance and vascular tone. The renal effects of circulating atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are distinct from the paracrine effects of vascular C-type natriuretic peptide (CNP). CNP is widely expressed throughout the vasculature and is found in particularly high concentrations in the endothelium. Recent studies demonstrate that CNP is a novel endothelium-derived hyperpolarising factor (EDHF) that complements the actions of other endothelial vasorelaxant mediators such as nitric oxide (NO) and prostacyclin. Since several cardiovascular disorders are associated with dysfunction of natriuretic peptide activity, selective modulation of the natriuretic peptide pathways represents an important therapeutic target; whilst this has been exploited to some degree in terms of ANP/BNP, the therapeutic potential of CNP has yet to be tapped. This review focuses on recent findings on the actions and mechanism of locally produced endothelial-derived CNP in the cardiovascular system and highlights many potential avenues for therapeutic intervention, via modulation of CNP-signalling, in cardiovascular disease.