The results of TKA during the past two decades have been reliable and favorable. While success rates are high, some patients experience pain and impaired function. This clinical scenario can be frustrating to both the patient and the surgeon who is accustomed to good outcomes. A systematic evaluation of the patient and arthroplasty can lead to a definitive diagnosis of the cause of the patient's symptoms. Problems can be caused by a broad spectrum of possible etiologies. It is helpful to divide the differential diagnosis into two broad categories: extra-articular and intra-articular etiologies. When trying to establish the diagnosis, it is important to approach the task in a systematic fashion. Evaluation must begin with a thorough history and physical examination. Laboratory tests and imaging studies can provide additional evidence supporting a particular diagnosis. Once the etiology has been established, symptomatic relief may be achieved with appropriate treatment including revision TKA. However, revision TKA that is performed for unexplained pain is associated with a low probability of success.