The risk of excessive bodyweight gain, glucose dysregulation and hyperlipidaemia is differentially increased by conventional and atypical antipsychotic drugs. Switching or combining agents may be sufficient in some cases, but in many instances additional drug treatment will be required. This includes oral antidiabetics, insulin and agents to treat hyperlipidaemia, hypertension and platelet dysfunction, among others. Numerous pharmacokinetic and pharmacodynamic interactions with the antipsychotics are possible, although few have been tested in formal studies. After reviewing the literature, the authors provide preliminary guidelines to assist clinicians in drug selection for this complex and fragile clinical population.