Introduction Clinicians have waited a long time for a ‘universal’ marker that may help them distinguish infected from non-infected total joint arthroplasties when doubts persist after using classical clinical and biological signs of infection. In recent years, synovial fluid biomarkers including leukocyte esterase, alpha-defensins, and CRP have shown promising results for the diagnosis of periprosthetic joint infections (PJIs). Areas covered This review provides an overview of the rational and the use of the Synovasure® alpha-defensin tests in patients with a suspicion of PJI. Using a systematic investigation by keywords, we looked for all citations (and the citations to these citations) of the selected papers. Expert opinion The Synovasure® alpha-defensin tests demonstrate high potential for the diagnosis of PJIs. However, the data currently available also show that the universal marker of infection in the settings of PJIs is still to be discovered.