Cathepsin S is a cysteine protease highly expressed in many type of cancers including colorectal, prostate, breast, and glioblastoma’s. It is involved in tumor progression through extracellular matrix remodeling. In recent years, antibody research specifically targeting Cathepsin S to block/inhibit tumorigenic effects were generated some positive preclinical data. This antagonistic antibody was demonstrating efficacy in multiple in vitro/in vivo cancer models both as a monotherapy and in combination with approved agents. This mini-review provides an overview of therapeutic antibody targeting Cathepsin S strategies in the last half decade, focusing on the rationale of cell-surface Cathepsin S targeted and their potential clinical application.