Despite the tremendous success obtained using the current pharmacotherapy, especially angiotensin (Ang)-converting enzyme (ACE) inhibitors (ACEis) and Ang II receptor blockers (ARBs), the prevalence of cardiovascular diseases (CVDs) remains high around the world. The overall death rate in the United States alone in 2005 was 278.9 per 100 000 people. 1 These unprecedented numbers have stimulated researchers to consider the development of new strategies and targets to control these diseases. Since its discovery, the renin-Ang system (RAS) has been considered an important target to manage the disturbances of the cardiovascular system. In fact, RAS blockers represent the main class of drugs in the treatment of hypertension and CVDs. 2 Recent genomic and proteomic studies have led to significant advances in our understanding of the RAS and in experimental methods for studying regulatory mechanisms influenced by the RAS. Thus, demonstrating the existence of a counterregulatory axis within the RAS, constituted by ACE2, Ang-(1-7), and the Mas receptor, has established a new concept for this system, that is, the classic narrow cascade formed by ACE, Ang II, and Ang II type 1 receptor (AT1) has been replaced by a flexible hormonal system with many bioactive peptides, receptors, enzymes, and interactions among these components. 2–4 Consequently, follow-up studies have revealed new possibilities and targets to better control CVD. In this review, we discuss the following:(1) the current status of the RAS with an emphasis on evidence for the existence of the ACE2/Ang-(1-7)/Mas axis;(2) the role of this axis in the pathophysiology of the cardiovascular, renal, pulmonary, and central nervous systems;(3) the potential of this protective axis for the development of novel CVD therapeutics; and (4) future perspectives.