Extracellular adenosine triphosphate (eATP) mediates pro-inflammatory responses by recruiting and activating inflammatory cells. eATP is hydrolyzed by CD39 to adenosine monophosphate (AMP), which is converted to the immunosuppressive nucleoside adenosine (ADO) by CD73. CD39 is the rate-limiting enzyme in this cascade and can be viewed as an immunological switch that shifts ATP-driven pro-inflammatory immune cell activity to an anti-inflammatory state mediated by ADO. CD39 is expressed by a broad range of immune cells and can be influenced by genetic and environmental factors. Accumulating evidence suggests that CD39 is involved in several pathophysiological events, such as inflammatory bowel diseases, sepsis, ischemia-reperfusion injury, allergic diseases, systemic lupus erythematosus, diabetes, and cancer. Here, we focus on the current understanding of CD39 in immunity, and presents a comprehensive picture of the multiple roles of CD39 in a variety of disorders.