Metastatic disease is responsible for most cancer lethality; therefore, understanding the intricate interplay among tumor cells, soluble factors, extracellular matrix (ECM), and host cells during cancer progression to metastasis is crucial to designing successful therapies [1]. Metastasis is formed when a cell, or a group of cells, leaves the original site of the primary tumor and establishes a new colony of tumor cells in a distant, anatomically separate, site in the body [1]. To form an overt metastasis, the cells must overcome the regulatory and physical constraints imposed by the tissue milieu and initiate proliferation and invasive growth. Proteases and their inhibitors and receptors, such as those that comprise the urokinase-type plasminogen activator (uPA) system, play a crucial role in determining the ability of tumor cells to metastasize (Figure 21.1). Interestingly, dissemination of tumor cells and metastatic growth promoted by uPA and its receptor (uPAR) may be caused not only by proteolysis but also by novel functions related to cell signaling necessary for tumor cells to migrate, survive, and proliferate in target organs [1, 2]. The role of uPAR in regulating cell motility, which appears to operate similarly in normal and tumor cells, has been covered recently in extensive reviews [3]. This chapter focuses on recent advances that focus on how the uPA system coordinates proteolysis and signal transduction for invasion, dissemination, survival, and mitogenesis during tumor progression.