The effectiveness of fibrinolysis results from the combination of regulated enzymatic activity and the physical properties of the fibrin scaffold. Physiologically, clots or thrombi are dissolved from within via internal lysis. In contrast, with therapeutic thrombolysis, lytic agents are introduced at one surface and lysis proceeds across the thrombus. In the latter case, there are complex changes that take place at the lysis front in a narrow zone. However, at the microscopic level the mechanisms for either general type of fibrinolysis appear to be similar. Fibrinolysis proceeds by fibers being transected laterally, rather than digestion of fibers by surface erosion from the outside. A molecular model to account for these observations together with what is known from the biochemical characterization of fibrinolysis involves the movement of plasmin laterally across fibers, binding to sites created by its own proteolytic activity. Fibrin clots can have a great diversity of structural, biological, physical, and chemical properties depending on the conditions of formation, and the rate and nature of fibrinolysis is related to these properties. In general, the rate of lysis appears to be faster for clots made up of thicker fibers than for clots made up of thinner fibers, but the lysis rate is not simply a function of fiber diameter and also depends on other physical properties of the clot. Platelet aggregation and clot retraction have a dramatic effect on the structure of fibrin and hence on fibrinolysis.