Kallikrein 5(KLK5), a serine protease encoded by the KLK5 gene, regulates skin desquamation by activating kallikrein proteases (e.g., KLK7) and degrading corneodesmosomes. In cancer, KLK5 exhibits dual roles: while overexpressed in colorectal and pancreatic cancers promotes metastasis via ECM degradation, its elevated expression in breast cancer suppresses tumor growth by inhibiting RhoA and modulating the mevalonate pathway. Dysregulated KLK5 activity drives inflammatory skin disorders through excessive cleavage of cathelicidins. Therapeutic strategies include covalent inhibitors for inflammatory diseases and KLK5-enhancing approaches in breast cancer. Serum KLK5 levels serve as biomarkers for fibrosis and cancer prognosis.