The major cephalic exocrine glands share many morphological and functional features and so can be simultaneously affected in certain autoimmune- and inherited disorders leading to glandular hypofunction. Phenotypic characterization of these exocrine glands is not only an interesting biological issue, but might also be of considerable clinical relevance. The major salivary and lacrimal glands might therefore be potential subjects of future cell-based regenerative/tissue engineering therapeutic approaches. In the present study, we described the expression of the stem and progenitor cell marker Prominin-1 and those of its paralogue, Prominin-2, in the three pairs of major salivary glands, i.e., submandibular-, major sublingual-, and parotid glands in adult mice. We have also documented their expression in the extraorbital lacrimal and meibomian glands (Glandulae tarsales) of the eyelid (Palpebra). Our analysis revealed that murine Prominin-1 and Prominin-2 were differentially expressed in these major cephalic exocrine organs. Expression of Prominin-1 was found to be associated with the duct system, while Prominin-2 expression was mostly, but not exclusively, found in the acinar compartment of these organs with marked differences among the various glands. Finally, we report that Prominin-2, like Prominin-1, is released into the human saliva associated with small membrane particles holding the potential for future diagnostic applications.