The urokinase plasminogen activator (uPA) and its receptor (uPAR) exert pleiotropic functions over the course of both physiological and pathological processes. Data generated in deficient mice have underlined how uPA not only has a key role in fibrinolysis but also modulates the development of protective immunity. By contrast, uPAR anchors uPA at the cell surface and, in addition to favoring extracellular matrix degradation, regulates cell migration, cell adhesion and cell proliferation, thus influencing the development of inflammatory and immune responses. Here, we review the expression and function of uPA and uPAR, and correlate their role in fibrinolysis with immune, infectious and proliferative disorders. This Review is the second in a series on interactions between haemostasis and inflammation.