Our research was based on studies involving N-methyl- D-aspartate type glutamate receptors in chicken-derived differentiating chondrocytes, as well as in healthy and pathological human pigment cells. Given that NMDARs primarily mediate Ca2+ currents, we focused on the changes of Ca2+ homeostasis. The experiments proved that NMDARs may have roles in the precisely regulated intracellular Ca2+ oscillations of chondroprogenitor cells, and NMDAR-evoked Ca2+ signals are associated with optimal chondrogenesis. NMDAR subunit protein expression profiles in melanoma cells, involving subcellular fractions, revealed major differences between melanocytes and melanoma cells with potentially functional nuclear NMDARs in the latter. In summary we demonstrated in vitro, for the first time, in non-excitable cells from outside the nervous system the presence of functional NMDARs (in differentiating chondrocytes), and the nuclear localisation of NMDARs (in melanoma cells). The former mediate Ca2+-dependent pathways that are indispensable to chondrogenesis, while the latter may have appeared as a result of malignant transformation.