“First-episode schizophrenia” is a clinical and research term that often is used to emphasize the special issues that arise when working with this patient population. The notion that schizophrenia has an inexorable downhill course or is a deteriorating illness is being challenged by more sophisticated understanding of what happens before the initial episode and new understanding of the interactions between biologic vulnerabilities and specific environmental risk during adolescence and early adulthood, such as marijuana use. While the incidence rate of “first-episode” will make this a relatively small percentage of a usual clinical caseload, it is a critically important time for the future course of the illness. The hope is that proper management during this critical period will favorably influence the long-term trajectory of outcome for this individual patient. A growing body of evidence suggests that certain approaches and interventions are more helpful than others, such as understanding of the overwhelming nature of the experience to patients and families, aiming to achieve a full and broad pharmacologic response to initial antipsychotic therapy, while also being on the lookout for vulnerability and extreme sensitivity to side effects, and to anticipate a high likelihood of premature medication discontinuation. Clinicians and treatment services should try to identify “first-episode” patients in time to be able to anticipate and address these issues.