Epilepsy, characterized by recurrent spontaneous seizures, is a heterogeneous group of brain diseases affecting over 70 million people worldwide. Major challenges in the management of epilepsy include its diagnosis and treatment. To date, video electroencephalogram (EEG) monitoring is the gold-standard diagnostic method, with no molecular biomarker in routine clinical use. Moreover, treatment based on anti-seizure medications (ASMs) remains ineffective in 30% of patients, and, even if seizure-suppressive, lacks disease-modifying potential. Current epilepsy research is, therefore, mainly focused on the identification of new drugs with a different mechanism of action effective in patients not responding to current ASMs. The vast heterogeneity of epilepsy syndromes, including differences in underlying pathology, comorbidities and disease progression, represents, however, a particular challenge in drug discovery. Optimal treatment most likely requires the identification of new drug targets combined with diagnostic methods to identify patients in need of a specific treatment. Purinergic signalling via extracellularly released ATP is increasingly recognized to contribute to brain hyperexcitability and, consequently, drugs targeting this signalling system have been proposed as a new therapeutic strategy for epilepsy. Among the purinergic ATP receptors, the P2X7 receptor (P2X7R) has attracted particular attention as a novel target for epilepsy treatment, with P2X7Rs contributing to unresponsiveness to ASMs and drugs targeting the P2X7R modulating acute seizure severity and suppressing seizures during epilepsy. In addition, P2X7R expression has been reported to be altered in the brain and circulation in experimental models of epilepsy and patients, making it both a potential therapeutic and diagnostic target. The present review provides an update on the newest findings regarding P2X7R-based treatments for epilepsy and discusses the potential of P2X7R as a mechanistic biomarker.