Some of the benefits of physical activity may result from effects on hemostasis. However, the increased burden of cardiovascular complications and sudden death occurring during and immediately after exercise prompts investigation to elucidate the biological relationship between physical exercise and hemostatic function. Although both the hemostatic and fibrinolytic systems are strongly influenced by physical exercise, the outcomes of available studies to date are biased by several confounding variables, including the subjects investigated, the type, intensity, and duration of the exercise, and the methods used for hemostatic evaluation. Considering these variables and attempting to synthesize the available data, it seems reasonable to conclude that the biological changes induced by physical activity are consistent with a mechanistic model where acute and strenuous exercise is associated with a transient hypercoagulability state, particularly in untrained individuals. This is mostly due to increased thrombin generation, platelet hyperreactivity, and increased activity of several coagulation factors, especially factor VIII and von Willebrand factor. Contextually, increased fibrinolytic activity has been frequently reported after exercise. Such changes, however, seem completely reversible, as trained subjects at rest show a partial exhaustion of platelet function in addition to values of several parameters of both the coagulation and fibrinolytic systems that are globally comparable with or even lower than those observed in the sedentary population. These adaptive changes might be beneficial in the long term, offering some protection against the risk of thrombosis and adverse cardiovascular events in physically active individuals.