Melanocytes are the neural crest–derived pigment-producing cells of the skin that possess dendrites. Yet little is known about how melanocyte dendrites receive and process information from neighboring cells. Here, using a co-culture system to interrogate the interaction between melanocyte dendrites and keratinocytes, we show that signals from neighboring keratinocytes trigger local compartmentalized Ca 2+ transients within the melanocyte dendrites. The localized dendritic Ca 2+ transients could be triggered by two keratinocyte-secreted factors, endothelin and acetylcholine, which acted via specific melanocyte receptors. Furthermore, compartmentalized Ca 2+ transients were also generated on discrete dendritic spine-like structures on the melanocytes. These spines were also present in intact human skin. Our findings provide insights into how melanocyte dendrites communicate with neighboring cells and offer a new model system for studying compartmentalized signaling in dendritic structures.