Proteomic analysis of the surfaceome, which is a subgroup of cell surface proteins, can provide valuable information for therapy, diagnosis, or prognosis in case of pathological alteration in malignant melanoma. Following determination of our surfaceome databases from three pigment cell cultures (epidermal melanocytes, in situ melanoma cells and invasive melanoma cells), the data were sorted based on each proteins' cellular activity and molecular functions. The differences found in the surfaceome of healthy vs malignant pigment cells can lead to the discovery of highly selective biomarkers on melanoma onset and progression. The systems biology approach enables a more targeted analysis of the pigment cell surfaceome database. Our results may give us a global picture on possible relationships between the identified proteins and networks involved in melanoma evolution.