Proteases are deeply involved in physiology and pathology. For most, the mechanism is well defined but several fail to display typical protease features (as is the case of the four proteases contained in fibronectin, the inhibitor-resistant mesotrypsin and the proteosomal deubiquitinating enzyme) or have unclear physiological function (such as calpain-like proteins, transthyretin and factor seven activating protease). In other cases, such as in peroxisomal processing proteases, although substrates are defined, the enzyme remains undiscovered. Furthermore, several proteases were identified in pathological conditions, namely secretases in Alzheimer's disease and gross cystic disease fluid protein 15 kDa in breast cancer, when most likely their physiological substrate is still hidden. Lastly, the evolutionary conservation of proteolytic enzymes raises questions related to the origin of biological events, such as the origin of cystein proteases and cell death responses. In this review we will discuss the above cryptic enzymes, as they will probably be relevant in the future.