Malignant melanoma is a common cancer form with an alarming increase of cases reported annually and, moreover, connected to bad prognosis if not discovered early. New treatments and new markers for early diagnosis are therefore much needed. We have in earlier studies seen that intracellular activities of lysosomal cysteine proteases in cancer cells from the breast and of other epithelial types, that seem critically connected to malignancy, can be dowregulated by externally added cystatin C. With the aim to find leads to new biomarkers for diagnosis and/or new treatment possibilities, we have therefore initiated a study to first carefully compare the cysteine protease/antiprotease system of previously studied breast MCF-7 cells with the three human melanoma cell lines MDA-MB-435S, A375 and C8161. The results were put into perspective by evaluating the expression patterns for members of the system in cancer patient databases, in order to define which enzymes and inhibitors of the system are relevant in melanoma. Secondly, we have studied the potential of different cystatins to internalize into the melanoma cells, to affect intracellular cysteine protease activities and, as a possible consequence, the properties of the cells to migrate and penetrate connective tissue.