Extracellular adenosine 5′-triphosphate (ATP) acts on many immune cells to promote inflammation. Conversely, the ATP metabolite adenosine is mainly an anti-inflammatory molecule. The ecto-enzymes CD39 and CD73 can dephosphorylate extracellular ATP to adenosine, thereby controlling this important pathway of immune modulation. Despite their established roles in the immune system, little is known of how CD39 and CD73 are themselves regulated. Recent data have shown that CD73 expression and adenosine generation are up-regulated by transforming growth factor-β, depending on the cytokine content of the local microenvironment. We review here these recent findings and discuss their implications in disease.