Adenosine 5'-triphosphate is known to function as a potent extracellular messenger, producing its effects via a distinct family of cell surface receptors. Different receptor subtypes have been shown to modulate different cellular functions such as proliferation, differentiation and apoptosis. We have investigated the functional expression and apoptotic action of the P2 X (7) receptor in human malignant melanoma tissue and cells. Incubation of cells with the potent P2 X (7) receptor agonist 2'-3'-O-(4-benzoyl-benzoyl) adenosine 5'-triphosphate leads to a decrease in cell number, which is dose-dependent and reversible by the antagonist 1-N,O-bis-[5-isoquinoline-sulfonyl]-N-methyl-L-tyrosyl)-4-phenyl-piperazine. Synthesis of the P2 X(7) receptor by these cells has been established by reverse transcriptase-polymerase chain reaction, immunohistochemistry, immunocytochemistry and cellular accumulation of the fluorescent DNA-binding dye YO-PRO-1. The P2 X(7) receptors have been shown to mediate apoptotic actions of extracellular nucleotides and represent a novel target for melanoma therapy.