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Adenosine has been proposed as an endogenous anticonvulsant which can play an important role in seizure ini- tiation, propagation and arrest. Extracellular ATP and adenosine are able to modulate synaptic activity through activation of P2 (P2X and P2Y) and P1 receptors (A1, A2A, A2B, and A3), respectively. Besides the release of adenosine per se, the levels of ATP and adenosine in the synaptic cleft are controlled by a complex cascade of cell surface-localized enzymes collectively known as ectonucleotidases. These enzymes are capable of hydrolyzing nucleoside triphosphates, diphos- phates and monophosphates to their respective nucleosides. There are four major families of ectonucleotidases: ecto- nucleoside triphosphate diphosphohydrolases (E-NTPDases), ecto-nucleotide pyrophosphatase/phosphodiesterases (E- NPPs), alkaline phosphatases and ecto-5'-nucleotidase. All these members have specific physiological functions in the brain. In this review, the involvement of ectonucleotidases in the pathophysiology of brain disorders, such as seizures and epilepsy, is discussed. A brief introduction about the general characteristics of these enzymes is followed by a discussion about the role of ectonucleotidases in epilepsy and seizures and the implications for future treatments.