Because multiple branded, alternative, and generic medications contain the same active ingredient, controversies sometimes arise regarding generic substitution. For patients, physicians, and nurses, the critical issue is whether generic medications are safe and effective. This article addresses the issue with regard to several anti-depressant, anticonvulsant, and antipsychotic medications. There is no consistent evidence that generic substitutes are less safe or effective than brand-name equivalents. Uncontrolled reports are subject to many confounding factors and biases. Relapses temporally associated with medication switches could be due to the change but are difficult to distinguish from the natural history of the treated condition. Adverse effects temporally associated with medication switches could also be attributable to the change, but they might also be explained as a type of "nocebo" effect. Randomized controlled blinded studies are necessary to evaluate causality; however, such studies typically have not supported uncontrolled reports that the safety or effectiveness of brand-name and generic drugs differ. It is still clinically prudent to monitor a patient whose medication has been switched.