Research on the regulatory actions of the renin-angioten-sin system (RAS) continues to provide a wealth of information on how cells maintain their internal homeostatic environment, regulate metabolic processes, and adapt or contribute to disease. Not that long ago, the active product of the system, angiotensin II (Ang II), was considered the single critical hormone product of an endocrine system involved in regulating blood volume and vascular tone. A revised concept emerged after the demonstration that renin and angiotensinogen (Aogen) are present in tissues. These findings suggested that the RAS is composed of dual, independently regulated, blood-borne and tissue systems. Today, a broader and more complex system is being revealed by advanced genetic and molecular tools, as well as by the outcome of clinical studies using medications selective for 1 of the proteins contributing to the generation of angiotensin peptides. Recognition that the RAS contains both a pressor and depressor arm in exerting regulatory functions on vascular tone and cellular signaling paved the way for the generation of an alternate hypothesis as to how an imbalance of their function contributes to cardiovascular disease. 1 This review summarizes the data supporting the hypothesis of a counterregulatory arm that, within the RAS, opposes the actions of Ang II. We build on these earlier discoveries to provide a new insight into an additional pathway in which an extended form of angiotensin I (Ang I), proangiotensin-12 (Ang-[1-12]), may be an alternate substrate for the production of the biological active angiotensins. A comprehensive evaluation of this topic cannot be achieved within the assigned space; therefore, only the key elements of the topic will be addressed, asking for indulgence in not providing a detailed listing of all of the published studies.