BACKGROUND Tapentadol hydrochloride is a centrally acting oral analgesic approved by the US Food and Drug Administration in November 2008 for the treatment of moderate to severe acute pain. It is available as immediate-release 50-, 75-, and 100-mg tablets. OBJECTIVE The purpose of this article is to review animal studies, pharmacokinetic studies, drug-drug interaction studies, and Phase II/III trials of tapentadol in various conditions producing moderate to severe pain. Efficacy and tolerability data from these studies are summarized. METHODS A search of MEDLINE and International Pharmaceutical Abstracts was conducted from January 2005 through June 30, 2009. Search terms included tapentadol, tapentadol hydrochloride, and (-)-(1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride. Relevant information was extracted from the identified articles, and the reference lists of these articles were reviewed for additional pertinent publications. The manufacturer was contacted for clinical trials, abstracts, and poster presentations that were not identified by the literature search. ClinicalTrials.gov was searched to identify recently completed studies. RESULTS Tapentadol produces analgesia through a dual mechanism of action: mu-opioid-receptor activation and norepinephrine reuptake inhibition. Its efficacy has been reported in a number of animal studies, as well as in Phase II/III clinical trials. Primary pain disorders in which efficacy has been reported include dental extraction pain, pain after bunionectomy surgery, osteoarthritis pain of the knee and hip, and low back pain. Major adverse effects reported in Phase II/III trials primarily involved the gastrointestinal system (2%-66% of subjects) and the central nervous system (4%-65% of subjects). The occurrence of gastrointestinal adverse effects appeared to be less frequent in tapentadol recipients than in those receiving oxycodone. CONCLUSIONS Tapentadol appears to be a well-tolerated and effective analgesic for the treatment of moderate to severe acute pain. Although not currently approved for the management of chronic pain, tapentadol has been reported to be effective in managing pain associated with osteoarthritis and low back pain.