Angiotensin converting enzyme-2 (ACE2) acts as the protective arm of the renin-angiotensin system (RAS). ACE2 counterbalances the actions of ACE by metabolising its catalytic product, angiotensin II (Ang II), to Ang-(1-7). ACE2 also metabolises a restricted number of other bioactive peptides, including apelin. Enhanced ACE2 expression may be protective in disease states including diabetes, cardiovascular disease, fibrosis and cancer. ACE2, like ACE, also plays important non-catalytic roles ranging from acting as viral receptor, as integrin receptor, and in regulation of amino acid transport. Relatively little is known, however, about the specific physiological factors regulating ACE2 and few transcriptional regulators have been identified. Here we show that ACE2 expression is increased under conditions of cell stress including hypoxic conditions, cytokine treatment and treatment with the AMP-mimic AICAR via mechanisms involving the NAD-dependent deacetylase SIRT1. Chromatin immunoprecipitation analysis demonstrated that SIRT1 was bound to the ACE2 promoter. AICAR treatment increased SIRT1 binding to the promoter. Inhibition of SIRT1 activity ablated the AICAR-induced increase in ACE2. As such it was established that the expression of the ACE2 transcript is controlled by the activity of SIRT1 under conditions of energy stress. ACE2 is also subject to microRNA regulation. These novel factors regulating ACE2 expression and functional activity may represent novel sites for modulating the angiotensin peptide levels, and other bioactive peptides, in cardiovascular and other diseases.