Cathepsin B is a lysosomal cysteine protease, contributing to vital cellular homeostatic processes including protein turnover, macroautophagy of damaged organelles, antigen presentation, and in the extracellular space, it takes part in tissue remodeling, prohormone processing, and activation. However, aberrant overexpression of cathepsin B and its enzymatic activity is associated with different pathological conditions, including cancer. Cathepsin B overexpression in tumor tissues makes this enzyme an important target for smart delivery systems, responsive to the activity of this enzyme. The generation of technologies which therapeutic effect is activated as a result of cathepsin B cleavage provides an opportunity for tumor-targeted therapy and controlled drug release. In this review, we summarized different technologies designed to improve current cancer treatments responsive to the activity of this enzyme that were shown to play a key role in disease progression and response to the treatment.