The story that led to the discovery of urokinase receptor (uPAR) system started in 1947 with the report of MacFarlane and Pilling who identified but did not named urokinase (uPA). Today, the uPAR system is recognized as one very important actor in tumourigenesis and is even considered as a valuable tumour marker. Its critical functions justify the important effort of translational research that has produced many inhibitors which unfortunately failed to be transferred in the clinic. However, the role of the uPAR system in cancer development should not shade the vital functions of this system in hematopoietic stem cells mobilization, cognitive functions including language development, inflammation, innate immunity, coagulation and fibrinolysis. All these topics are covered in this special theme issue of the journal Current Pharmaceutical Design that comprises 9 reviews written by leading scientists. Other aspects are also embraced by additional articles including the first attempt to depict the complete atlas of the uPAR interactome, and the regulation of the uPAR system by the LDL receptor-related protein-1 (LRP-1).