The diagnosis of periprosthetic joint infections (PJIs) has traditionally been performed by obtaining a history and physical exam, measuring serology, and performing microbiology analysis of synovial fluid and tissue samples. The measurement of serum biomarkers, such as the erythrocyte sedimentation rate and the C-reactive protein (CRP), is routinely used to diagnose PJI. However, these markers are elevated in all inflammatory conditions, necessitating the need for more specific biomarkers to diagnose PJI. Serum biomarkers such as procalcitonin, interleukin (IL)-6, tumor necrosis factor (TNF)-α, short-chain exocellular lipoteichoic acid, soluble intercellular adhesion molecule-1, and monocyte chemoattractant protein-1 may be more specific to PJI. Synovial fluid biomarkers elevated in PJI include cytokines such as IL-1β, IL-6, IL-8, IL-17, TNF-α, interferon-δ, and vascular endothelial growth factor. More specific synovial fluid biomarkers include synovial CRP, α-defensin, human β-defensin-2 (HBD-2) and HBD-3, leukocyte esterase, and cathelicidin LL-37. These biomarkers are the future for sensitive and specific diagnosis of PJI.