The serine protease urokinase-type plasminogen activator, its inhibitor and its receptor are considered the most valuable prognostic cancer biomarkers relevant to predict the clinical course of cancer patients and their response to cancer therapy. They are also among the few biomarkers that have been evaluated successfully in clinical studies for their clinical utility, for the most part in early breast cancer. This work provides an overview of the molecular mechanisms and clinical outlook of this important proteolytic system.