More than 2% of all human genes are coding for a complex system of more than 700 proteases and protease inhibitors. Amongst them, serine proteases play extraordinary diverse functions in different physiological and pathological processes. The Human Airway Trypsin-like protease (HAT), also referred to as TMPRSS11D and serine 11D, belongs to the emerging family of cell surface proteolytic enzymes, the type II transmembrane serine proteases (TTSPs). Through the cleavage of its four major identified substrates, HAT triggers specific responses, notably in epithelial cells, within the pericellular and extracellular environment, including notably inflammatory cytokine production, inflammatory cell recruitment or anticoagulant processes. This review summarizes the potential role of this recently described protease in mediating cell surface proteolytic events, to highlight the structural features, proteolytic activity and regulation, including the expression profile of HAT and discuss its possible roles in respiratory physiology and disease.