Asymmmetric dimethylarginine (ADMA) and monomethyl arginine (L-NMMA) are endogenously produced amino acids that inhibit all three isoforms of nitric oxide synthase (NOS) [1]. ADMA accumulates in various disease states including renal failure, diabetes and pulmonary hypertension, and its concentration in plasma is strongly predictive of premature cardiovascular disease and death [2-4]. Both L-NMMA and ADMA are eliminated largely through active metabolism by dimethylarginine dimethylaminohydrolase (DDAH) [5] and thus DDAH dysfunction may be a crucial unifying feature of increased cardiovascular risk. However, despite considerable interest in this pathway and the role of ADMA as a novel risk factor, there is little evidence to support a causal role in pathophysiology. Here we reveal the structure of human DDAH-1 and probe the function of DDAH-1 both by deleting the DDAH-1 gene in mice and by use of designed specific inhibitors which we demonstrate by crystallography bind to the active site of human DDAH. We show that loss of DDAH activity leads to accumulation of ADMA and reduction in NO signalling. This in turn causes vascular pathophysiology including endothelial dysfunction, increased systemic vascular resistance and elevated systemic and pulmonary blood pressure.