Replacement of native joints aims to restore patients’ quality of life by relieving pain and improving joint function. While periprosthetic joint infection (PJI) affects a small percentage of patients, with an estimated incidence of 1–9% following primary total joint replacement, this postoperative complication necessitates a lengthy hospitalisation, extended antibiotic treatment and further surgery. It is highlighted that establishing the correct diagnosis of periprosthetic infections is critical in order for clinicians to avoid unnecessary treatments in patients with aseptic failure. Of note, the PJI diagnosis could not purely rely upon clinical manifestations given the fact that heterogeneity in host factors (e.g., age and comorbidities), variability in infection period, difference in anatomical location of the involved joint and discrepancies in pathogenicity/virulence of the causative organisms may confound the clinical picture. Furthermore, intra-operative contamination is considered to be the main culprit that can result in early or delayed infection, with the hematogenous spread being the most prevalent mode. To elaborate, early and hematogenous infections often start suddenly, whereas chronic late infections are induced by less virulent bacteria and tend to manifest in a more quiescent manner. Last but not least, viruses and fungal microorganisms exert a role in PJI pathogenesis.