Adenosine (ADO) is an immunosuppressive molecule with multiple functions in different human organs. ADO is released through the concerted action of surface molecules endowed with enzymatic functions, that belong to two different adenosinergic pathways. The canonical pathway is started by CD39, that converts ATP to AMP. On the other hand, the non-canonical pathway metabolizes NAD+ to ADPR, through the action of CD38. The latter byproduct is then converted to AMP by CD203a/PC-1. Both pathways converge to CD73, that fully degrades AMP to the final product ADO. In this Review we take into account the most relevant finding regarding the expression of ectoenzymes belonging to both adenosinergic pathways in different cell types, including regulatory cell subsets and neoplastic cells. Moreover, we summarize the role of these molecules in different physiological and pathological settings. Finally, we discuss potential therapeutic application of specific inhibitors of ectoenzymes and/or ADO receptors.