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Schizophrenia spectrum disorders (SSD) constitute a group of psychiatric illnesses which frequently lead to persisting mental impairment. Although some patients show a clinical course with few episodes and good long-term outcome, the course of the disease is often chronic and unfavorable. Long-term treatment (LTT) of SSD pertains to the postacute stabilization period and the remission period following pharmacological and psychosocial therapy of an acute illness episode. This article provides an overview of treatment recommendations concerning long-term pharmacotherapy, dealing with side effects, treatment of non-response and therapy resistance and the treatment of psychiatric comorbidities. Furthermore, an overview of non-pharmacological treatment options is presented. An integrated therapeutic setting combining evidence-based pharmacotherapy, psychosocial interventions, and supportive therapies is recommended for optimal LTT of SSD. Considering the limited financial resources available in the healthcare system, one of the major challenges is to provide patients with access to the evidence-based treatment options available.