Formulation substitution using generic preparations for innovator products is becoming increasingly prevalent in the name of cost containment. So long as generic substitutes are truly clinically equivalent to the innovator compounds, patient harm should not ensue. However, for drugs with a narrow therapeutic index, serious concerns about generic equivalence are beginning to arise, particularly with neurologic, immunosuppressive, anticoagulant, and antiarrhythmic drugs. This article reviews the guidelines used to approve a generic compound and their limitations and provides case-based information as to the adverse clinical consequences-arrhythmia recurrence, proarrhythmia, and death-that have now been reported in association with generic substitution of antiarrhythmic compounds. Additionally, guidelines for allowance or avoidance of antiarrhythmic drug formulation substitution are suggested.