Conflicting views abound on the peripheral neurotransmitter and neuromodulator roles of purine compounds. Substantial organ- and species-related variations have become apparent. There is, however, a body of compelling evidence for such roles, if not so broad and ubiquitous as those envisioned (7) for the central nervous system. The variations may in part be attributable to the neuroeffector synaptic geometry. The transmitter concentration found at the postsynaptic membrane drops precipitously with increase in the synaptic cleft (85). Where the cleft is narrow, a purine may serve as the primary or sole transmitter (purinergic nerve) and presynaptic modulator. Alternatively, from nonpurinergic (e.g. adrenergic) nerves a purine may be released, possibly ATP by exocytosis, to act as a cotransmitter. It may also serve as pre- and post-synaptic modulator, potentially with a contribution from postsynaptic release (Figure 1). The purine could conceivably diffuse and affect other varicosities. Where the cleft is wide, the postsynaptic concentration of the neurogenic purine may be too low to permit a transmitter or postsynaptic modulator function. The concentration of the nonpurine transmitter may also be insufficient to elicit a significant postsynaptic purine release. The neuronally released purine may, however, presynaptically exert inhibition of transmitter release much as in a narrow cleft. It seems, therefore, that the origin of synaptic purines and their function, be it transmitter, cotransmitter, or modulator, are dictated at least in part by the characteristics of the purine pools, purinergic receptors, and synaptic configuration, which await further assessment.