Extracellular metabolism of ATP and other nucleotides has expanded significantly in the past decade. Receptors for ATP are present on most cells in vertebrates, and other nucleotides like ADP, UTP, and diadenosine polyphosphates also function as signaling molecules. Extracellular signaling requires mechanisms to inactivate signals, including reuptake, hydrolysis, and salvage. Nucleotides are hydrolyzed to nucleosides and free phosphate, which can be recycled. Adenosine, a hydrolysis product of ATP, can activate additional functions. The discovery of novel ectoenzymes has changed our understanding of extracellular nucleotide hydrolysis. Previously, it was thought that specific enzymes existed for ATP, ADP, or both. However, new enzyme families with overlapping substrate specificities and tissue distributions have been identified. These include E-NTPDase, E-NPP, alkaline phosphatases, and ecto-5'-nucleotidase, which have broad tissue distributions. Other enzymes, such as those hydrolyzing diadenosine polyphosphates, NAD+, and nucleotide-converting enzymes, have also been described. ATPase activity is found in association with NCAM and alpha-sarcoglycan. Ectonucleotidases are membrane-bound, with catalytic sites facing the extracellular medium. They require divalent cations and an alkaline pH. Their Km values are in the lower micromolar range. These enzymes terminate nucleotide signaling and facilitate purine salvage, especially in tissues with high extracellular nucleotide levels. Some enzymes may have multiple functions, including cell adhesion and transmembrane receptor functions. The E-NTPDase family includes enzymes that hydrolyze nucleoside 5'-triphosphates and 5'-diphosphates. They share conserved domains and a binding motif. Members are divided into two groups based on membrane topology. NTPDase1-4 have transmembrane domains, while NTPDase5 is soluble. These enzymes have varying preferences for nucleotides, with NTPDase2 preferring ATP. All require divalent cations for activity.Extracellular metabolism of ATP and other nucleotides has expanded significantly in the past decade. Receptors for ATP are present on most cells in vertebrates, and other nucleotides like ADP, UTP, and diadenosine polyphosphates also function as signaling molecules. Extracellular signaling requires mechanisms to inactivate signals, including reuptake, hydrolysis, and salvage. Nucleotides are hydrolyzed to nucleosides and free phosphate, which can be recycled. Adenosine, a hydrolysis product of ATP, can activate additional functions. The discovery of novel ectoenzymes has changed our understanding of extracellular nucleotide hydrolysis. Previously, it was thought that specific enzymes existed for ATP, ADP, or both. However, new enzyme families with overlapping substrate specificities and tissue distributions have been identified. These include E-NTPDase, E-NPP, alkaline phosphatases, and ecto-5'-nucleotidase, which have broad tissue distributions. Other enzymes, such as those hydrolyzing diadenosine polyphosphates, NAD+, and nucleotide-converting enzymes, have also been described. ATPase activity is found in association with NCAM and alpha-sarcoglycan. Ectonucleotidases are membrane-bound, with catalytic sites facing the extracellular medium. They require divalent cations and an alkaline pH. Their Km values are in the lower micromolar range. These enzymes terminate nucleotide signaling and facilitate purine salvage, especially in tissues with high extracellular nucleotide levels. Some enzymes may have multiple functions, including cell adhesion and transmembrane receptor functions. The E-NTPDase family includes enzymes that hydrolyze nucleoside 5'-triphosphates and 5'-diphosphates. They share conserved domains and a binding motif. Members are divided into two groups based on membrane topology. NTPDase1-4 have transmembrane domains, while NTPDase5 is soluble. These enzymes have varying preferences for nucleotides, with NTPDase2 preferring ATP. All require divalent cations for activity.