Generic substitution has become a common practice since the late 1970s. Because of the increased use of generic alternatives and concerns about the Food and Drug Administration standards for bioequivalency, especially with respect to narrow therapeutic index drugs, the awareness and attitudes of prescribing physicians to generic drugs and generic substitution are important. A questionnaire designed to assess attitudes, beliefs, knowledge, and experiences with generic drugs and generic substitution was sent to 3639 physicians nationwide. Cluster analysis was used to identify attitudinal groups that were then analyzed with respect to differences in beliefs, knowledge, and experience with generic drugs. Perceptions of the therapeutic index for 15 branded drugs and comfort in substituting those products with generic alternatives were assessed. Physicians were classified into prosubstitution and antisubstitution groups, with a further division of antisubstitution physicians according to whether they felt influenced by outside pressures to substitute. Significant differences were found between the prosubstitution and antisubstitution groups with respect to beliefs about and experiences with generics and knowledge of the Food and Drug Administration bioequivalency standards. Of particular significance was the low percentage (17%) of physicians who correctly identified the Food and Drug Administration standards for bioequivalency. Prosubstitution physicians generally rated therapeutic indexes as wider than antisubstitution physicians. Physicians in all groups identified similar products they believed were not appropriate for substitution. Attitudes toward generic substitution are related to prescribing behaviors, beliefs about and experience with generic substitution, and perceptions of therapeutic index and comfort with substitution. Physicians need to understand the issues surrounding generic substitution and remain empowered to influence decisions to substitute.