Tissue kallikrein has been suggested to be involved in blood pressure regulation and in protection against hypertension. However, this hypothesis remains debated. Recently, murine genetic models of kallikrein deficiency have been engineered and partial genetic deficiency in kallikrein activity has been characterized in humans. Studies in kallikrein-deficient mice indicate that kallikrein indeed influences blood pressure in the setting of mineralocorticoid excess and salt retention but not in normotensive animals and in high renin hypertension. These observations suggest that kallikrein can have antihypertensive function in physiological situations where sodium retention can trigger blood pressure elevation.