Chromogranin-A (CGA), which accounts for more than half the soluble matrix protein in secretory granules of various neuroendocrine cells, has a wide spectrum of potential biological roles and is considered an important marker of the diffuse neuroendocrine system (DNES). Light and electron microscopic immunohistochemistry of mammalian skin revealed that Merkel cells are exclusively CGA-immunoreactive (ir) and that the immunoreaction is localized in the secretory granules. This finding supports the classification of the Merkel cell as a member of the DNES. The CGA immunoreactivity was restricted to Merkel cells of pigs and humans. In human embryonic skin, CGA was expressed in Merkel cells as early as week 11 of gestation. The antisera differed in their ability to stain Merkel cells in different species and developmental stages, reflecting a variable chemical coding for CGA. CGA probably represents a precursor for smaller regulatory peptides or acts as a messenger on its own on various target tissues, suggesting a neurosecretory function of the Merkel cell.