More than 50 years after the introduction of modern pharmacotherapies for schizophrenia, there remains a tremendous need for therapeutic advances. A second generation of antipsychotic drugs, introduced over the past 15 years, has provided uncertain advantages over the first-generation drugs. This paper reviews the designs of studies that evaluate the effectiveness of putative antipsychotic drugs. Data from the trials needed to achieve regulatory approval do not meet all the needs of clinicians and policy makers. Practical and large, simple trials that evaluate the comparative effectiveness of antipsychotic drugs in real-world settings can help to meet these needs once a drug has reached the market.