St14 is a type II transmembrane serine protease that contains a cytoplasm N-terminal domain, a stem domain, and a serine protease catalytic domain. It is primarily synthesized as an inactive zymogen and co-expressed with the cognate inhibitor hepatocyte growth factor inhibitor (HAI) in epithelial cells. Accumulating evidence suggests that it plays critical roles in pre-implant embryonic compaction, placental development, as well as epidermal barrier formation after activation. The homologous ablation of St14 in mouse underlies the neonatal death at 48h for severe deficiency of the epidermal barrier. It has also been considered as a prognostic marker of epithelial cancers as it is involved in cancer metastasis and invasion in multiple ways by activating several kinds of substrates, such as... hepatocyte growth factor (HGF), urokinase-type Plasminogen activator (uPA). Notably, the strict regulation of St14 by HAIs is found to play a profound role in all of these activities. However, very little is currently understood about the mechanisms that downregulate St14 gene expression in early neonatal mortality. Herein we summarize the current knowledge of the regulation network and the understanding of the biological functions of St14.