Cathepsin K (catK) is a lysosomal cysteine protease with strong collagenolytic activity that mediates bone resorption in osteoclasts. Recently, catK expression has been reported in skin and lung fibroblasts, which suggests a role in maintaining homeostasis of the extracellular matrix outside of bone. Matrix degradation is a pivotal step in tumor invasion and metastasis. As other proteases, in particular matrix metalloproteinases and some cathepsins, but not catK, have been described to mediate melanoma invasion, we studied catK in melanoma. Immunostaining revealed strong catK expression in most primary melanomas and all cutaneous melanoma metastases. Melanocytic nevi also demonstrated catK expression, but it was less intense than in melanomas. Melanoma lines express both the pro- and the active form of catK and internalize extracellular collagen into lysosomes. Inhibition of catK greatly reduced melanoma cell invasion through Matrigel basement membrane matrix and increased detection of internalized collagen. We suggest that catK may play an important role in melanoma invasion and metastasis by mediating intracellular degradation of matrix proteins after phagocytosis. Clinical use of catK inhibitors, a class of medication currently in clinical trials for the treatment of osteoporosis, may be a promising avenue for the treatment of melanoma.