For human malignant melanoma, no pattern of oncogene activation has yet been identified which consistently occurs in the malignant cells. In order to better understand the transformation process, we studied the overall gene expression at the protein level in human melanoma cells in vitro by two-dimensional gel electrophoresis. For that, four established cell lines, MEWO, M5, SKMEL13, and IGR39, were used and compared with newly established cultures of normal human melanocytes. Considerable variations in the protein patterns of the different melanoma cell lines were found, whereas the patterns of normal human melanocytes correlated fairly well with each other. With respect to the expression of single proteins, we identified four major proteins which were consistently found in cultured melanocytes and stringently repressed in the four melanoma cell lines examined. On the other hand, induction of new proteins in the different melanoma cell lines was found to be less stringent and also less uniform. We propose that malignant transformation of melanocytes may be more associated with the suppression of melanocytic proteins rather than with new expression of melanoma specific proteins.