Youth experiencing psychosis also frequently misuse substances, making it clinically challenging to differentiate substance-induced psychosis (SIP) from a primary psychotic disorder (PPD), which has important implications for management and prognosis. This article presents practical considerations related to differentiating SIP from PPD, including information on substances associated with symptoms of psychosis. Recommendations for management of SIP are also reviewed, including screening for and treating comorbid substance use disorders and using evidence-based medication and psychosocial interventions.