A diagnosis of infection in the painful primary total knee replacement is not always a straightforward endeavor. No single, fail-proof diagnostic study for infection exists. Often multiple diagnostic studies that include imaging, blood work, and joint aspiration as well as history and physical examination need to be considered. Infection may not always be determined before surgery, in which case intraoperative frozen sections can help to confirm infection or refute a negative workup. Treatment options vary, depending on the timing in the infection process and the source of the infection and may consist of simpler treatment courses, such as irrigation, débridement, and polyethylene exchange, to more complex treatment courses, such as two-stage revision with an antibiotic spacer to fusion or amputation. The orthopaedic surgeon uses an essential armamentarium of diagnostic and treatment options to determine the presence of infection and tailor the individual treatment of each patient.