The nociceptive nervous system and the immune system serve to defend and alarm the host of imminent or actual damage. However, persistent or recurring exposure of neurons to activated immune cells is associated with an increase in painful behavior following experimental neuropathic injuries. Our understanding of the functional consequences of immune cell-neuron interaction is still incomplete. The purpose of this review is to focus on a seriously detrimental consequence of chronic activation of these two systems, by discussing the contributions of microglia and polymorphonuclear neutrophils to neuropathic pain following experimental spinal cord injury or peripheral nerve injury. Identification of molecules mediating pro-nociceptive signaling between immune cells and neurons, as well as the distinction between neuroprotective versus neuroexcitatory effects of activated immune cells, may be useful in the development of pharmacotherapy for the management of chronic pain and restoration of the beneficial alarm function of pain.