The cystatins are a super family of cysteine protease inhibitors which are ubiquitous in their biologic occurrence. Cystatin C, a type II cystatin, is primarily a secreted protein found in most biological fluids. Besides acting as inhibitors of cathepsin, the cystatins have been found to have some non-inhibitor related functions and multiple physiological roles. Much interest has been generated for the cystatins as metastasis “suppressor-like” proteins, as they have been shown to inhibit metastasis for multiple cancer types. The sites and actions of the cystatins related to tumor suppressor actions are still unclear, however. In this work, we have examined the uptake of cystatin by metastatic melanoma cells in culture. Our results indicate cystatin uptake is mediated by a non-canonical endocytotic pathway in B16 murine melanoma cells.