Asenapine (Saphris(®), Sycrest(®)) is an atypical antipsychotic that is administered sublingually twice daily and is approved for schizophrenia in the USA, Japan and other countries, but not in the EU. This article reviews the pharmacology, clinical efficacy and tolerability profile of asenapine in the treatment of adults with schizophrenia. Clinical trials with asenapine have demonstrated efficacy in terms of both positive and negative symptoms of schizophrenia, although findings have not always been consistent. Across three short-term (6-week) studies in acute schizophrenia (including one in Asian patients), asenapine was generally superior to placebo and had broadly similar efficacy to active controls in improving total scores on the Positive and Negative Syndrome Scale. A meta-analysis of four short-term trials with asenapine (that also included a negative study and a failed trial) also showed significant benefit with asenapine over placebo. In longer-term trials and extensions (up to ≈3 years' duration), asenapine was effective relative to placebo in preventing relapse in schizophrenia, but was less effective than olanzapine in patients with schizophrenia or schizoaffective disorder (according to intent-to-treat LOCF analysis). However, in two trials in patients with persistent negative symptoms of schizophrenia, asenapine and olanzapine were similarly effective in reducing negative symptoms at week 26, with asenapine providing better results than olanzapine at week 52 in one of the extensions. The most frequently reported adverse events with asenapine are somnolence, akathisia and oral hypoesthesia. Although potentially associated with more extrapyramidal symptoms, asenapine appears to have less weight gain and metabolic effects than some other antipsychotic agents, such as olanzapine.