Clozapine’s effectiveness for treatment-resistant schizophrenia and mania, and its anti-aggressive properties, has led to trials for younger and older patients with severe mental disorders, and for those with intellectual disability (ID) who have treatment-resistant psychosis or nonpsychotic behavioral disorders. There is a paucity of double-blind data supporting some of these uses, but a compelling picture of efficacy based on case series and a small number of clinical trials. The common theme for these patient groups is managing tolerability concerns through adjustment of initial titration, use of plasma clozapine levels, and careful tracking of adverse effects. Pregnant women represent a patient population with a different set of issues; however, recent developments in the literature on major congenital malformations and first-trimester antipsychotic exposure support the conclusion that atypical antipsychotics as a class are not associated with increased risk. This finding is consistent with the available clozapine case data, and thereby allows clinicians to focus their energies on monitoring for maternal gestational diabetes, and minimization of postnatal exposure to avoid excessive sedation in the newborn. Clinicians should be familiar with the risk nomenclature and data on psychotropics during breastfeeding as a matter of routine clinical competence; however, due to risk of neutropenia, clozapine is the only antipsychotic that is absolutely contraindicated in breastfeeding women.