The relationship between substance use disorders and schizophrenia has long intrigued mental health researchers and clinicians. When individuals develop psychosis in the context of substance use, what does that tell us in terms of etiopathophysiology and likely prognosis and outcome? How does one differentiate schizophrenia from substance-induced psychotic disorder? What are the treatment and prognostic implications of that distinction? In this presentation, the above questions will be addressed and clinical characteristics that enable differential diagnosis will be outlined.