Hypertension is the most serious health problems and associated with many cardiovascular risks causing the death of a large number of populations. It has become life threating burden to the growing population in both developing and developed country. Many combination therapies are prescribed for the management of hypertension. This prudent approach resulted in overburden of medications associated with adverse effects and patient non-compliance. Exploration of the new potential targets led to the brain Renin-Angiotensin System (RAS) and vasopeptidase. Brain RAS inhibitor decreases arginine-vasopressin and decreasing sympathetic tone. Vasopeptidase inhibitors are the dual blockers of angiotensin-converting enzyme and prohibit the degradation of natriuretic peptidase by enzyme neuronal endopeptidase. Overall, this review gives a glimpse of new targets with recognizable clinical implications in lowering blood pressure.