Altered expression and activity of proteases is a key event in cancer, particularly in relation to invasion, modification of the extracellular matrix and metastasis. The transmembrane protease, serine 4 (TMPRSS4) is closely related to other cancer-associated proteases, such as hepsin, TMPRSS2 and matriptase. We review in this study up-to-date information about expression, role, regulation and clinical relevance of TMPRSS4 in cancer. Increased expression of this protease is associated with acquisition of epithelial to mesenchymal transition, invasion and metastasis in vivo. Signalling in cancer cells involves upregulation of integrin-α5 (ITG-α5) and urokinase-type plasminogen activator (uPA), downregulation of E-cadherin and activation of uPA enzymatic activity at the plasma membrane, as well as phosphorylation of FAK, Src, Akt and ERK1/2 intracellularly. Upregulation of miR-205 hinders the protumorigenic effects elicited by TMPRSS4 through restoration of E-cadherin levels and direct targeting of ITG-α5. High levels of TMPRSS4 have been found in several types of solid tumours in patients, and association with poor prognosis has been consistently described. On the basis of this information and the structural characteristics of this druggable protease, we suggest that TMPRSS4 could be a novel potential therapeutic target in solid tumours.British Journal of Cancer advance online publication, 9 September 2014; doi:10.1038/bjc.2014.403 www.bjcancer.com.