Antigen (Ag) processing by major histocompatibility complex class II (MHC) class II molecules is tightly linked with the proteases of the endosomal/lysosomal system. Cysteine (Cys) cathepsins, which constitute a major portion of this proteolytic system, have been found to have essential roles in both Ag processing and maturation of the MHC class II molecules. In this review, we will cover some specific functions of individual Cys cathepsins and particularly those most relevant to the immune system.