Introduction: Patients with treatment-resistant schizophrenia receiving clozapine therapy are at risk of potentially serious complications in the general hospital setting, due to the complex pharmacokinetic and pharmacodynamic profile of clozapine. There is currently lack of guidance on managing this patient group, which we aim to address in this article. Method: Common clinical challenges that face clinicians who care for clozapine patients in the general hospital are summarized, and recommendations made based on the available literature and clinical experience. Conclusion: Early collaborative management between consultation-liaison psychiatry and other clinical teams in the general hospital are paramount to improve clinical outcomes and avoid serious complications in this patient group.