P2X receptors are homo- or heterotrimeric ATP-gated cation channels that assemble from seven subunits, P2X1-P2X7. To our knowledge, no drug that acts on the P2X1 or P2X2 receptors in the CNS or elsewhere in the body has been approved, nor is there such a drug currently in clinical trials. Only a few non-drug-like antagonists such as the suramin derivatives NF449 and NF770 and the anthraquinone derivative PSB-1011 are available as pharmacological tools to block the P2X1 and P2X2 receptors, respectively. The focus of this review is twofold. First, we review the current knowledge of the role of the P2X1 and P2X2 receptors in normal and pathological CNS functions as inferred from experiments with wild-type, P2X1 knockout and P2X2 knockout mice. From the available data we conclude that the P2X1 and P2X2 receptors may have therapeutic potential as targets for neuroprotective drugs. Second, we review the impact of the recent resolution of the crystal structure of the zebrafish P2X4 receptor in the apo closed state and the ATP-bound open state. The P2X4 crystal structure opens the exciting possibility to generate P2X homology models for a rational drug design. In silico docking experiments with a homology-modeled rat P2X2 receptor revealed an almost perfect coordination of the nanomolar potent P2X2 antagonist NF770 through strong polar interactions between the acidic groups of NF770 and the mostly basic groups of the ATP-binding pocket. Such structural information might be helpful in designing drug-like compounds that function as selective P2X receptor antagonists without the pharmacokinetic limitations of the currently available antagonists.