Lysosomal cysteine proteinases, also known as cysteine cathepsins (Cats), belong to the papain family of proteinases, and share a similar protein structure and mechanism of action. However, subtle structural differences between these cathepsins, e.g. Cats B, H and L, give rise to potentially important variations in substrate specificity and differences in inhibition by their endogenous inhibitors, the cystatins, stefins and kininogens, under physiological and pathological conditions. Alterations in expression of Cat B and Cat L have been observed at various levels in malignant human tumor tissue compared to normal and benign tissue counterparts. We proposed that an imbalance between cathepsins and cystatins, associated with the metastatic tumor cell phenotype, may facilitate tumor cell invasion and metastasis and be responsible for early relapse of the disease after removal of the primary tumor. The results of our initial investigations on cysteine cathepsins and their endogenous inhibitors in human breast, lung and head and neck carcinomas, as well as in body fluids of melanoma and colorectal carcinoma bearing patients, have indeed shown their high prognostic impact for the survival of these patients.