The promise of cancer immunotherapy has not been translated into clinical successes, in large part because of tumor-associated immune suppression that blocks effective antitumor immunity. Recent findings show a tumor-induced immunosuppressive mechanism, whereby tumor-derived CD73 functions as an ecto-enzyme to produce extracellular adenosine, which promotes tumor growth by limiting antitumor T-cell immunity via adenosine receptor signaling. Results with small molecule inhibitors, or monoclonal antibodies targeting CD73 in murine tumor models, suggest that targeted CD73 therapy is an important alternative and realistic approach to effective control of tumor growth. In particular, it helps T-cell–based therapy by enhancing the adaptive immune response machinery, which may increase the function of tumor-infiltrating T lymphocytes, and subsequently lead to improved survival in cancer patients. Cancer Res; 70(16); 6407–11. ©2010 AACR.