Atypical antipsychotics offer broader efficacy and improved tolerability compared with conventional agents. Many patients currently treated with conventional antipsychotics continue to experience persistent symptoms or troublesome side effects and may benefit from a change to one of the newer atypical agents. There are also significant differences in the side-effect profiles of the atypicals, such that a switch from one atypical agent to another could offer advantages to many patients. Unfortunately, many clinicians remain uncertain about the switching process and are reluctant to initiate change. The aim of this review is to identify the indications for a switch in antipsychotic therapy with a focus on recent switching data for the atypical antipsychotic, quetiapine. The clinical aspects of quetiapine's receptor binding characteristics are reviewed including the implications of the low D(2) antagonist properties that make quetiapine the treatment of choice when EPS persists with other atypical antipsychotics. Practical guidelines are given for managing the process of changeover, for avoiding pitfalls and for maximizing the chances of a successful switch. For example, when managing the antipsychotic crossover, it is important to consider the psychological effects of switching arising from symptom and side-effect changes. Finally, advice is provided on the assessments necessary when evaluating the success of a change in therapy, together with guidance on the optimal duration of treatment trials.