Low-molecular-weight heparins (LMWHs) are polypharmacologic drugs used to treat thrombotic and cardiovascular disorders. These drugs are manufactured using different chemical and enzymatic methods, resulting in products with distinct chemical and pharmacologic profiles. Generic LMWHs have been introduced in Asia and South America, and several generic suppliers are seeking regulatory approval in the United States and the European Union. For simple small-molecule drugs, generic drugs have the same chemical structure, potency, and bioavailability as the innovator drug. Applying this definition to complex biological products such as the LMWHs has proved difficult. One major issue is defining appropriate criteria to demonstrate bioequivalence; pharmacopoeial specifications alone appear to be inadequate. Whereas available generic versions of LMWHs exhibit similar molecular and pharmacopoeial profiles, marked differences in their biological and pharmacologic behavior have been noted. Preliminary studies have demonstrated differences in terms of anti-Xa activity and tissue factor pathway inhibitor release after subcutaneous administration, as well as antiplatelet and profibrinolytic effects. The current data emphasize the need to consider multiple functional parameters when defining bioequivalence of biologic drugs with complex structures and activities and also underscore the importance of further pharmacologic studies involving animal models and human clinical trials. The U.S. Food and Drug Administration and the European Medicine Evaluation Agency are currently developing guidelines for the acceptance of biosimilar agents including LMWHs. Until such guidelines are complete, generic interchange may not be feasible.