Recent clinical trials have raised questions over the perceived advantages of second-generation 'atypical' antipsychotics over those from the first generation. An atypical antipsychotic in its original sense is one that lacks extrapyramidal side effects. However, the addition of other clinical features to the original concept of atypicality, such as efficacy against negative and cognitive symptoms, seems to have become a feature of searches for novel antipsychotics in the past two decades. Although this approach has led to some therapeutic advances, we propose that it has also hampered antipsychotic drug research and that reframing the concept of atypicality could have a key role in making genuine breakthroughs in schizophrenia therapy.