Research during the past two decades supports a complex role for neuropeptide tyrosine (NPY) and two of its associated receptors, the Y1 receptor and the Y2 receptor, in the modulation of pain, in addition to regeneration and survival mechanisms at the spinal level. Thus, NPY has been shown to both cause and reduce pain, in addition to having biphasic effects. Recent research has focused on the distribution of the spinal NPY-mediated system. Here, we propose various possible scenarios for the role of NPY in pain processing, based on its actions at different sites (axon versus cell body), through different receptors (Y1 receptor versus Y2 receptor) and/or types of neuron (ganglion neurons and intraganglionic cross-excitation versus interneurons versus projection neurons).