Efforts to understand how the immune system can influence nervous system function are hampered by the complexity of mammalian nervous and immune systems. The marine mollusc Aplysia californica has recently emerged as a useful model system to investigate cellular mechanisms underlying neural-immune interactions. Aplysia has a relatively simple, well-characterized nervous system that is accessible for intracellular recording. Moreover, it shares with mammals basic cellular defensive responses to non-self or wounded-self, i.e. the accumulation of numerous defense cells (hemocytes) around foreign objects or at injured sites. We have shown that the excitability of a population of nociceptive sensory neurons in Aplysia can be influenced by the presence of hemocytes close to their axons. These sensory neurons also show profound, long-lasting increases in their excitability following axonal injury. Hemocytes are attracted to injured sites on peripheral nerves, and we have developed an in vitro nervous system-hemocyte coculture system to demonstrate that hemocytes can also influence the expression of this injury-induced sensory hyperexcitability. Immunoreactive interleukin-1 (IL-1) and tumor necrosis factor have been identified in Aplysia. Preliminary in vitro studies showing that IL-1 can modulate the expression of injury-induced sensory hyperexcitability raise the interesting possibility that hemocyte-derived cytokine-like factors can modulate sensory neuron functioning. The relevance of this work to more phylogenetically advanced organisms is also discussed.