Cysteine cathepsins are lysosomal peptidases involved on one hand in general intracellular protein degradation and, on the other, in the regulation of a number of specific physiological processes. Their integral role in extracellular matrix degradation and in processing growth factors, hormones and adhesion proteins is a driving force in cancer progression, triggering tumor proliferation, invasion, angiogenesis and metastasis. Cancer stem cells are proposed to be a main factor of tumor initialization, heterogeneity and resistance to therapy. Recent studies have uncovered increased expression, aberrant localization and disturbed functions of certain cysteine cathepsins in these cells, in particular in glioblastoma stem cells. Here, we review the research that have underlined the expression patterns and roles of cysteine cathepsins in cancer stem cells, and emphasize the involvement of cysteine cathepsins in caspase-independent cell death and in regulating interaction between cancer stem cells and immune cells such as natural killer cells.