The idea of classifying various cells into a diffuse endocrine system, first conceived before 1940, was given a solid cytological and cytochemical basis by Pearse in the 1960’s with the advent of immunohistochemical techniques. Subsequent data have confirmed the common expression of many proteins in these cells and moreover demonstrated that several of these are typically neuronal, expressed neither by non-neural nor by other endocrine or exocrine cells. The enzymes responsable for amine precursor uptake or synthesis, enzymes such as neurone specific enolase, the growth associated protein SCG10 and GAP-43, the chromogranin family of acidic proteins, the capacity to synthesize neurofilaments, the neural cell adhesion molecules NCAM and L1, and many of the proteins implicated in neurotransmission or associated with synaptic vesicles, such as synaptophysin, synaptotagmin, VAMP, SV2, SNAP-25 and syntaxin, are found in both neurones and these neuroendocrine relatives. More recent data reveal, however, that all members of this system do not express all typically neuronal proteins equally, including the cell adhesion molecule L1, the growth associated protein GAP-43, and SNAP-25. This differential expression suggests that although all these endocrine cells can be classified together in a single system widely dispersed throughout the body, some of them have a phenotype more closely resembling that of neurones.