Urokinase type plasminogen activator (uPA) activates plasminogen to plasmin and is often associated with diseases where tissue remodeling is essential (e.g. cancer, macular degeneration, atherosclerosis). We discuss some of the mechanisms of uPA action in diseases, and evidence that some of the early uPA inhibitors can modulate the progression of these diseases. Recently, a number of research groups have discovered, with the aid of structure-based design, a new generation of uPA inhibitors. These inhibitors are much more potent and selective than their predecessors. We will review this progress here, and give particular attention to the structural rationale associated with these observed increases in potency and selectivity.