Most clinical data for antipsychotics come from studies designed to test the efficacy and safety of the drugs under ideal conditions, in limited subgroups of patients. In contrast, practical clinical trials (PCTs) are designed to test the effectiveness of different treatment options under conditions that more accurately reflect actual clinical practice. Consequently, PCTs are able to provide information that can be utilized by healthcare providers and other decision makers. Characteristics of PCTs include a clinically relevant question, a representative sample of patients and practice settings, sufficient power to identify modest relevant effects, randomization to protect against bias, uncertainty regarding the outcome of treatment, assessment and treatment protocols that enact best clinical practices, simple and relevant outcomes, and limited subject and investigator burden. The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) research program is an example of a PCT. The CATIE study illustrates how PCTs, when properly designed, might be helpful in informing clinical decision making. Because the CATIE study was designed to reflect the effectiveness of antipsychotics under naturalistic clinical conditions, its results should have particular applicability to the arena of clinical practice. This article provides a discussion of the differences between efficacy and effectiveness studies. In assessing the practical utility of results from the CATIE study, much can be learned on how to shape future studies of effectiveness so as to better generate data that are applicable to the “real world.”