Periprosthetic joint infection remains one of the most common failure modes following total hip and total knee arthroplasty. As such, a systematic and cost effective approach to the evaluation and work-up of a patient with a suspected periprosthetic joint infection should be undertaken in every patient with a painful total joint. Although we have many diagnostic tools, a history and physical remain the most important. Many of the current laboratory tests are indirect measure of infection, lack specificity for diagnosis of infection, but serve as sensitive and cost effective screening tools. In addition, a new definition of periprosthetic infection helps to standardize the diagnosis. Biomarkers hold the promise of improved specificity and are becoming increasingly popular as a diagnostic tool.