Signaling molecules like the angiotensins or opioid peptides have been found in both nervous and immune systems of invertebrates. They can also be found free in the hemolymph, suggesting that they are acting as classical hormones. In this regard, enzymatic processing of these peptides has also been described and found to be similar to that found in vertebrates, e.g. renin-angiotensin system. Furthermore, the amino acid sequence of the invertebrate opioid and angiotensin gene products reveal a high sequence identity with their mammalian counterparts. These peptides are flanked by proteolytic signal-processing sites for known enzymes, i.e., aspartyl protease, neutral endopeptidase 24.11 and angiotensin converting enzyme, confirming that the invertebrate neuropeptide precursors are processed in a manner similar to that described in mammals. In the leech and other parasites we surmise that these signaling systems, because of their great similarity, are employed to escape host immunosurveillance. Taken together, the data indicate that, as in mammals, these signaling molecules can act as hormones operating in a neuroendocrine and immunoregulatory manner. Given their presence in similar tissues, i.e., neural, they constitute a primitive diffuse neuroendocrine system.