The World Health Organization reported that in 2003 cardio and cerebrovascular diseases such as heart failure, myocardial infarction, hypertension, coronary artery disease and stroke make up to 16.7 million (29%) of total worldwide deaths (www.who.int). In Europe these diseases are responsible for 27% to 56% of total deaths and are estimated to require 53% of the total health expenditures. Despite extensive efforts to develop therapeutic strategies for these diseases the results are not yet satisfying and there is a need for further development of new pharmacological treatments. The function of nitric oxide (NO), which is produced in the healthy endothelium, has been summarized as “anti-atherosclerotic”. Therefore, endothelial dysfunction, i.e. the inability of the endothelium to produce NO and subsequent impaired vasorelaxation leads to pathophysiological conditions, such as atherosclerosis, which is one of the major pathogenic factors contributing to the cardio and cerebrovascular clinical endpoints mentioned above. Under certain conditions, nitric oxide synthase has been shown to generate nitrogen species that are chemically distinct from NO. Among these, nitroxyl (HNO), the one-electron-reduced form of NO, has attracted scientific interest for its unique cardio and cerebrovascular effects that are pharmacologically different from NO. These effects make HNO a very promising pharmacological agent to be used in the treatment of cardio and cerebrovascular diseases. Furthermore, we recently found that HNO can be formed from myoloperoxidase (MPO) in vitro. MPO is upregulated under inflammatory conditions and inflammation is one major pathophysiological mechanism in cardio and cerebrovascular diseases. Thus, the basis to promote HNO as a therapeutic strategy is the understanding of the underlying mechanisms of action, signaling pathways and function in the in vivo system under physiological and pathophysiological conditions.