The chapter discusses the extracellular metabolism of ATP and other nucleotides, highlighting the significant expansion in the field of signaling via extracellular nucleotides over the past decade. It emphasizes that almost every cell in a vertebrate organism expresses surface receptors for ATP and other nucleotides, such as ADP, UTP, UDP, and diadenosine polyphosphates. The chapter explains the mechanisms by which these signaling molecules are inactivated, including receptor desensitization, downregulation, and hydrolysis. Nucleotides are hydrolyzed by an extracellular cascade, forming nucleosides and free phosphates, which can be recycled for resynthesis. The chapter also reviews the molecular cloning and functional characterization of novel families of ectoenzymes capable of hydrolyzing ATP and other nucleotides, revising the previous simplistic view of single enzymes for each substrate. It introduces the E-NTPDase family, which includes members with broad substrate specificity and tissue distribution, and discusses their molecular and functional characteristics. The chapter provides details on the catalytic activities and substrate preferences of specific E-NTPDase family members, such as NTPDase1 to NTPDase4, and their dependence on divalent cations for catalytic activity.The chapter discusses the extracellular metabolism of ATP and other nucleotides, highlighting the significant expansion in the field of signaling via extracellular nucleotides over the past decade. It emphasizes that almost every cell in a vertebrate organism expresses surface receptors for ATP and other nucleotides, such as ADP, UTP, UDP, and diadenosine polyphosphates. The chapter explains the mechanisms by which these signaling molecules are inactivated, including receptor desensitization, downregulation, and hydrolysis. Nucleotides are hydrolyzed by an extracellular cascade, forming nucleosides and free phosphates, which can be recycled for resynthesis. The chapter also reviews the molecular cloning and functional characterization of novel families of ectoenzymes capable of hydrolyzing ATP and other nucleotides, revising the previous simplistic view of single enzymes for each substrate. It introduces the E-NTPDase family, which includes members with broad substrate specificity and tissue distribution, and discusses their molecular and functional characteristics. The chapter provides details on the catalytic activities and substrate preferences of specific E-NTPDase family members, such as NTPDase1 to NTPDase4, and their dependence on divalent cations for catalytic activity.