The aim of this study was to review the efficacy and safety of atypical antipsychotics, comparing within class, placebo, or compared to another active treatment for delirium. A literature search was conducted using PubMed, EMBASE, and the Cochrane database (1 January 1990–5 November 2012). Selection criteria for review were prospective, controlled studies (comparison studies), using validated delirium rating scales as outcome measures. A total of six prospective, randomized controlled studies were included in the review. It was found that atypical antipsychotics are effective and safe in treating delirium, even though there seemed to be no difference between each agent. In particular, comparison studies with haloperidol showed that the efficacy of atypical antipsychotics was similar to that of low-dose haloperidol. It was concluded that atypical antipsychotics appear to be effective and tolerable in the management of delirium, even though the evidence is limited.