CD73 is a ubiquitously expressed glycosylphosphatidylinositol (GPI)-anchored glycoprotein that converts extracellular adenosine 5'-monophosphate (AMP) to adenosine. CD73 couples closely with ecto-apyrase (CD39), which supplies the AMP substrate via sequential dephosphorylation of extracellular ATP. CD73-generated adenosine functions in an autocrine and paracrine manner to control numerous physiological responses by activating one of four subtypes of G-protein-coupled adenosine receptors: A1R, A2AR, A2BR, and A3R. Missense mutations in the CD73-encoding gene NT5E cause the rare, adult-onset vascular disease named ‘arterial calcifications due to deficiency of CD73’ (ACDC). Aside from direct human disease involvement, cellular and animal model studies have revealed key functions of CD73 in tissue homeostasis and pathophysiologic responses in the cardiovascular and central nervous system, as well as epithelial tissues, including the lung, kidney and liver. This review covers CD73 functions in multiple organ systems, with a focus on novel findings from the last 3-5 years.