Adenosine receptors are a powerful therapeutic target for regulating epileptic seizures. As a homeostatic bioenergetic network regulator, adenosine is perfectly suited to establish or restore an ongoing balance between excitation and inhibition, and its anticonvulsant efficacy is well established. There is evidence for the involvement of multiple adenosine receptor subtypes in epilepsy, but in particular the adenosine A1 receptor subtype can powerfully and bidirectionally regulate seizure activity. Mechanisms that regulate adenosine itself are increasingly appreciated as targets to thus influence receptor activity and seizure propensity. Taken together, established evidence for the powerful potential of adenosine-based epilepsy therapies and new strategies to influence receptor activity can combine to capitalize on this endogenous homeostatic neuromodulator.