Total knee arthroplasty (TKA) has been associated with notable improvements in health-related quality of life of patients with end-stage knee arthritis. Although most patients experience substantial symptomatic relief after TKA, up to 19% of patients are unsatisfied with their outcome. With the dramatic, projected increase in the number of TKAs performed annually, it is crucial to appreciate the various modes of failure associated with this procedure. A comprehensive understanding of the symptomatology and thorough clinical examination aid in identifying the etiology of ongoing knee pain. Ancillary testing including conventional laboratory analyses, imaging studies, and diagnostic injections supplement a thorough history and physical examination. In addition, novel laboratory markers, RNA/DNA-based tests, and novel imaging modalities are emerging as beneficial tools in evaluating patients with a painful TKA. A well-structured, algorithmic approach in the management of these patients is essential in correctly diagnosing the patient and optimizing clinical outcomes.