Kallikrein-K1 is the main kinin-forming enzyme in organs in resting condition and in several pathological situations whereas angiotensin I-converting enzyme/kininase II (ACE) is the main kinin-inactivating enzyme in the circulation. Both ACE and K1 activity levels are genetic traits in man. Recent research based mainly on human genetic studies and study of genetically modified mice has documented the physiological role of K1 in the circulation, and also refined understanding of the role of ACE. Kallikrein-K1 is synthesized in arteries and involved in flow-induced vasodilatation. Endothelial ACE synthesis displays strong vessel and organ specificity modulating bioavailability of angiotensins and kinins locally. In pathological situations resulting from hemodynamic, ischemic, or metabolic insult to the cardiovascular system and the kidney K1 and kinins exert critical end-organ protective action and K1 deficiency results in severe worsening of the conditions, at least in the mouse. On the opposite, genetically high ACE level is associated with increased risk of developing ischemic and diabetic cardiac or renal diseases and worsened prognosis of these diseases. The association has been well-documented clinically while causality was established by ACE gene titration in mice. Studies suggest that reduced bioavailability of kinins is prominently involved in the detrimental effect of K1 deficiency or high ACE activity in diseases. Kinins are involved in the therapeutic effect of both ACE inhibitors and angiotensin II AT1 receptor blockers. Based on these findings, a new therapeutic hypothesis focused on selective pharmacological activation of kinin receptors has been launched. Proof of concept was obtained by using prototypic agonists in experimental ischemic and diabetic diseases in mice.