Most patients can safely and effectively be started on clozapine in community treatment settings. However, it is difficult to start some patients on clozapine because they have challenges to participating in community treatment or because they are at high risk of serious side effects. This includes patients who are likely to benefit substantially from the medication. Clinicians should consider hospitalizing patients when there are challenges to starting clozapine in the community, such as a history of suicide attempts, violence or self-injurious behavior; ongoing severe substance use; disorganization; severe cognitive impairment; or social or economic problems, such as homelessness, limited access to laboratory or pharmacy, or limited support from families and other caregivers. Patients can be at high risk due to side effects if they have a relevant serious medical illness, concurrent problematic medications, or previously experienced a serious side effect, such as myocarditis, severe neutropenia, or poorly controlled seizures. If hospitalization is not feasible in these patients, it is sometimes possible to start clozapine in the community with frequent contacts and adequate supports. When planning to discharge a patient from the hospital on clozapine, it is critical that outpatient visits have been scheduled, the patient has more than enough medication to last until their first outpatient visit, and the patient and outpatient provider are enrolled in the clozapine REMS program.