Objectives of our research program are to test the hypothesis that genetic targeting of the renin-angiotensin system (RAS) would lead to a gene therapy strategy for a long-term control of hypertension. Antisense inhibitin of the RAS was test to determine the validity of this concept. We established that a single systemic administration of retroviral vector containing angiotensin II type 1 receptor antisense (AT1R-AS) prevents development of high blood pressure (BP) and related-cardiac and vascular pathophysiology for life in both genetic and non-genetic rat molds of hypertension. Next, we studied the effects of ACE2 overexpression on hypertension-linked cardiac hypertrophy and remodeling. ACE2 is a newly discovered member of the RAS and is responsible for the conversion of Ang II to cardio-protective Ang (1–7). Lentiviral vector-mediated overexpression of ACE2 prevented Ang II infusion-induced cardiac hypertrophy, left ventricular wall thickness, myocardial and perivascular fibrosis without significant effects on BP. Taken together, these observations provide conceptual support for gene therapy for hypertension and CVD. Current advances in the use of this technology for MI-induced cardiac remodeling and HF and future direction of this strategy will be discussed.