Adherence to treatment is a major determinant of outcome in bipolar disorder. Poor insight, attitudes towards treatment, and poor understanding of medications and the illness can all lead to reduced adherence. Nonadherence and partial adherence both also appear to play a significant role in relapse and recurrence. Clinicians can address the problem of poor adherence by ensuring medication administration. Assured administration can be accomplished with long-acting atypical antipsychotic medications. Case series and naturalistic trials utilizing first generation antipsychotics suggest that depot antipsychotics are effective in reducing relapse in bipolar illness. Controlled studies with second generation agents confirm this impression. Depot antipsychotics, including long-acting first- and second-generation agents, can be important adjuncts in the long-term management of bipolar illness.