The common occurrence of comorbid substance misuse and other psychiatric disorders has challenged the diagnostic and therapeutic skills of professionals concerned with the care of patients with these dual disorders. Combined pharmacological and psychological treatment approaches have evolved empirically drawing upon standard treatments with emphasis on psychosocial approaches to substance misuse for psychotic disorders and pharmacological approaches for mood disorders. Advances in the biology of both disorders have started to inform their psychopharmacology. The specific role of atypical antipscychotics is highlighted. Further studies of the biology of comorbidity will impact the use of effective pharmaceuticals such as clozapine with dual effects on schizophrenia and substance misuse.