The enzymatic activities of CD39 and CD73 play strategic roles in modulating purinergic signals to immune cells by converting ATP/ADP to AMP and AMP to adenosine, respectively. This shift from an ATP-driven proinflammatory environment to an adenosine-induced anti-inflammatory milieu is crucial for maintaining immune homeostasis. The expression and activity of CD39 and CD73 dynamically change in response to various pathophysiological contexts, and altering these catabolic mechanisms can influence the outcomes of several diseases, including AIDS, autoimmune diseases, infections, atherosclerosis, ischemia-reperfusion injury, and cancer. CD39 and CD73 are expressed on various immune cells, such as Tregs, neutrophils, monocytes, macrophages, dendritic cells, and endothelial cells, where they regulate immune responses and inflammation. Infections, particularly those caused by parasites, fungi, and bacteria, often exploit CD39/CD73 to generate an adenosine-rich environment that helps them evade immune surveillance. Conversely, CD39/CD73 can also curb infections by producing adenosine, which inhibits pathogen growth and reduces inflammation. In autoimmune diseases, such as multiple sclerosis and rheumatoid arthritis, altered CD39/CD73 functions contribute to disease progression. In ischemia-reperfusion injury, adenosine produced by CD39/CD73 protects tissues from hypoxic and ischemic insults. In atherosclerosis, CD39 and CD73 regulate purinergic signaling, influencing the initiation and progression of atheroma formation. In diabetes, CD39 and CD73 may have a balancing regulatory role in inflammatory processes. In cancer, CD39/CD73 complexes participate in tumor immunoescape and promote tumor growth and metastasis. Overall, the CD39/CD73 pathway is a critical checkpoint in shaping immune responses and inflammation, and its modulation represents a promising therapeutic strategy for managing various disorders.The enzymatic activities of CD39 and CD73 play strategic roles in modulating purinergic signals to immune cells by converting ATP/ADP to AMP and AMP to adenosine, respectively. This shift from an ATP-driven proinflammatory environment to an adenosine-induced anti-inflammatory milieu is crucial for maintaining immune homeostasis. The expression and activity of CD39 and CD73 dynamically change in response to various pathophysiological contexts, and altering these catabolic mechanisms can influence the outcomes of several diseases, including AIDS, autoimmune diseases, infections, atherosclerosis, ischemia-reperfusion injury, and cancer. CD39 and CD73 are expressed on various immune cells, such as Tregs, neutrophils, monocytes, macrophages, dendritic cells, and endothelial cells, where they regulate immune responses and inflammation. Infections, particularly those caused by parasites, fungi, and bacteria, often exploit CD39/CD73 to generate an adenosine-rich environment that helps them evade immune surveillance. Conversely, CD39/CD73 can also curb infections by producing adenosine, which inhibits pathogen growth and reduces inflammation. In autoimmune diseases, such as multiple sclerosis and rheumatoid arthritis, altered CD39/CD73 functions contribute to disease progression. In ischemia-reperfusion injury, adenosine produced by CD39/CD73 protects tissues from hypoxic and ischemic insults. In atherosclerosis, CD39 and CD73 regulate purinergic signaling, influencing the initiation and progression of atheroma formation. In diabetes, CD39 and CD73 may have a balancing regulatory role in inflammatory processes. In cancer, CD39/CD73 complexes participate in tumor immunoescape and promote tumor growth and metastasis. Overall, the CD39/CD73 pathway is a critical checkpoint in shaping immune responses and inflammation, and its modulation represents a promising therapeutic strategy for managing various disorders.