The identification of patients at high risk of relapse is currently one of the most important issues in breast cancer research. However, the selection of high-risk patients continues to be difficult due to the unpredictable course of this disease. Axillary lymph node status is currently recognized as the best clinical discriminant between good and poor prognosis, yet almost 30% of node-negative patients and 65% of node-positive patients will experience a relapse. Additional prognostic markers are therefore urgently needed. Since metastatic disease is the main cause of cancer patient morbidity and mortality, the measurement of molecules functionally involved in the regulation of tumor invasion and metastasis is attractive as a means to predict prognosis. Cancer invasion is a complex process in which degradation of the extracellular matrix plays a crucial role. This degradation is accomplished by the concerted action of several proteolytic enzyme systems, including generation of plasmin by the urokinase pathway of plasminogen activation, matrix metalloproteases, and other extracellular proteases. Increased expression and secretion of urokinase plasminogen activator (uPA) strongly correlates with the malignant phenotype of many types of cells, and the central role of uPA in tumor invasion is now well established. This review will focus on the prognostic impact of components of the urokinase plasminogen activation system in breast cancer with emphasize on methodological issues.