Merkel cells are post-mitotic cells scattered throughout the epidermis of vertebrates. They are particularly interesting because of the close connections that they develop with sensory nerve endings and the number of peptides they can secrete. These features suggest that they may make an important contribution to skin homeostasis and cutaneous nerve development. However, these cells remain mysterious because they are difficult to study. They have not been successfully cultured and cannot be isolated, severely hampering molecular biology and functional analysis. Merkel cells probably originate in the neural crest of avians and mammalians, and their “spontaneous” appearance in the epidermis may be caused by a neuron-independent epidermal differentiation process. Their functions are still unclear: they take part in mechanoreception or at least interact with neurons, but little is known about their interactions with other epidermal cells. This review provides a new look at these least-known cells of the skin. The numerous peptides they synthesize and release may allow them to communicate with many cells other than neurons, and it is plausible that Merkel cells play a key role in skin physiology and physiopathology.