No one would dispute that intracellular enzymes such as kinases and phosphatases play critical roles in regulating the development, activation, differentiation, and survival of lymphocytes1. However, it is less well appreciated that cells of the immune system also express many membrane-associated ecto-enzymes that have the potential to regulate immune cell function. Ecto-enzymes have their active sites located on the outside of the cell and therefore must utilize substrates that are found in the extracellular milieu. Some of these enzymes, such as CD26, act as peptidases, while others, including CD73, CD38, CD39, ART2, and PC-1, utilize nucleotides as substrates. Although it was proposed that these nucleotide-utilizing enzymes might be involved in salvaging purines2 or in generating products such as ATP, ADP, and adenosine that function as signaling molecules for purinergic receptors3, until recently very little was known about the functional roles these enzymes might play during immune responses. However, in the last 10 years it has become clear that many of these enzymes play very important roles in regulating the survival, activation, and effector function of leukocytes4. Our laboratory has spent the last several years assessing the role of one of these ectoenzymes, CD38, in immune responses. In this article, we will review our recent work, focusing on the role that CD38 plays in regulating innate and adaptive immune responses.