Thrombosis is the collective term for diseases caused by the localized accumulation of circulating blood elements within the vasculature that result in vessel occlusion. Conventional antithrombotic drugs can inhibit thrombus growth by targeting coagulation pathways (e.g., heparin, warfarin) or platelet-dependent mechanisms (e.g., aspirin, clopidogrel). Thrombolytic agents (e.g., streptokinase) are used to degrade thrombi in situ, thereby restoring the blood flow. Despite advances, the search for new strategies continues because existing treatments impair hemostasis, and must be administered at dose levels that do not achieve maximum efficacy. Only a few drugs are used at markedly efficacious doses, for short periods of time in closely watched clinical situations, such as interventional cardiology and surgery. Ideally, new targets for therapy would lead to the development of agents that are specific for thrombus-forming mechanisms without affecting hemostasis. In the absence of such agents, new products should preferentially inhibit the thrombotic process at doses that are relatively safe. The symptomatology of naturally occurring or experimentally-induced alterations of relevant hemostatic pathways can serve as basis for target selection. Hemostatic disorders that are compatible with life, do not pose a significantly increased risk of bleeding, but potentially protect against thrombosis provide guidance for rational design strategies. Theoretical considerations and recent experimental data suggest that: 1) inhibition of intrinsic coagulation pathway activity, 2) reduction of circulating platelet count, or 3) activation or enhancement of endogenous protein C or thrombolytic pathways could improve antithrombotic therapy.