There is currently no effective cure for trigeminal neuralgia (TN) - a relatively common disease that causes long-term pain in patients. Previous research has shown that ionotropic ATP signaling through excitatory and calcium-permeable P2X receptor channels plays a critical role in pathological pain generation and maintenance. In this paper, we review several hypotheses on the pathogenic mechanisms underlying TN. We further discuss pathways or agents that can target P2X expression in TN, thereby affecting pain induction and maintenance.