CD73 or ecto-5'-nucleotidase (5'-NT) is a widely expressed ecto-enzyme which catalyzes the dephosphorylation of AMP and other nucleoside monophosphates. CD73 participates in purine salvage through this enzymatic activity, supplying cells with precursors for energy metabolism and nucleic acid biosynthesis. As an enzyme that produces adenosine, CD73 can also regulate adenosine receptor engagement in many tissues. However, CD73 also has functions independent of its enzyme activity. Like many glycosyl phosphatidylinositol (GPI)-anchored molecules, it transmits potent activation signals in T cells when ligated by antibodies. Less compelling evidence suggests that CD73 may function as a cell adhesion molecule. In the human immune system, CD73 is expressed on subsets of T and B cells, on germinal center follicular dendritic cells, and on thymic medullary reticular fibroblasts and epithelial cells. Many challenging areas remain to be explored before the role of CD73 in the immune system will be fully understood. These include an evaluation of the role of adenosine receptors in lymphoid development, the identification of physiological CD73 ligands, a functional assessment of the GPI anchor, and an analysis of the intricate cell-type-specific and developmental regulation of CD73 expression.