Cysteine cathepsins are a versatile group of proteolytic enzymes with a broad spectrum of substrates. They are known to reside within endo-lysosomes where they acquire optimal conditions for proteolytic activity and substrate cleavage. However, cysteine cathepsins have been detected in locations other than the canonical compartments of the endocytic pathway. Namely, cysteine cathepsins are often secreted from cells in either proteolytically inactive proform or as mature and active enzymes, this may happen in both physiological and pathological conditions. Moreover, cytosolic and nuclear forms of cysteine cathepsins have been described and are currently an emerging field of basic research aiming at understanding their functions in such unexpected cellular locations. We will summarize the canonical pathways of biosynthesis and transport of cysteine cathepsins in epithelial cells. We will further describe how cysteine cathepsins can reach unexpected locations such as the extracellular space, or the cytosol and the nuclear matrix. This presentation will focus in particular on the experimental approaches that enable trafficking studies in intestine and thyroid epithelial and carcinoma cells. We will explain canonical and unexpected or altered cysteine cathepsin transport by their tagging with green fluorescent proteins. Such experiments, when combined with application of activity based probes, are also suited to visualize cysteine cathepsin activites on the spot. This helps to better understand where substrates meet with the cysteine cathepsins, and which outcomes can be perceived from such encounters. Thus, scenarios are discussed on how cysteine cathepsins support specific processing and exhaustive degradation of internalized substrates within endo-lysosomes, how they involve in proteolytic modification of their substrates located in the peri-cellular environment, and how alternate forms acting in the nucleus may even trigger faster progression through the cell cycle.