Infection is becoming the most important as well as the most devastating mechanism of prosthetic joint failure. The incidence is increasing because the absolute number of patients operated is increasing and because more often very sick, debilitated and immunocompromised patients are operated. The trend reveals a further increase in the years to come. Diagnosis may be very easy in case of high grade processes, but also extremely difficult in some other instances. Misdiagnosing infection leads to repeated early failures that are distressing for patients as well as surgeons. To avoid failures related to misdiagnosed prosthetic joint infections a step-wise algorithm of action is proposed and the diagnostic strength of the steps discussed. The key point is to select potential candidates to define the probability of an ongoing infection and then to select the tools to strengthen the suspicion. Further procedures are based on the analysis of the pseudo-synovial fluid obtained by aspiration. Diagnostic conclusions form the basis for treatment decisions.