Decades ago lysosomal cysteine peptidases – the cathepsins, have been suggested as promotors of malignant processes. In collaboration with Tamara Lah we extensively evaluated their role in development and progression of different types of cancer. By developing specific reagents and diagnostic assays we assessed their values to predict diagnosis, prognosis and response to therapy, paving the way towards personalized treatment of cancer patients. Our research was later extended on new modes of anti-cancer therapy by developing new inhibitors of cysteine cathepsins and delivery systems for specific targeting of harmful peptidases. More recently, cysteine cathepsins have been recognized as important players of anti-tumor immune response. They can be explored by tumor cells to prevent their recognition by immune cells or to impair immune cell cytotoxicity and consequently tumor cell killing. The lecture will present key achievements of our collaborative work and suggest directions for further activities.