Prosthetic joint replacement surgery is performed with increasing frequency. Overall the incidence of prosthetic joint infection (PJI) and subsequently prosthesis revision failure is estimated to be between 1 and 3%. Differentiating infection from aseptic mechanical loosening, which is the most common cause of prosthetic failure, is especially important because of different types of therapeutic management. Despite a thorough patient history, physical examination, multiple diagnostic tests and complex algorithms, differentiating PJI from aseptic loosening remains challenging. Among imaging modalities, radiographs are neither sensitive nor specific and cross-sectional imaging techniques, such as computed tomography and magnetic resonance imaging, are limited by hardware-induced artefacts. Radionuclide imaging reflects functional rather than anatomical changes and is not hampered by the presence of a metallic joint prosthesis. As a result scintigraphy is currently the modality of choice in the investigation of suspected PJI. Unfortunately, there is no true consensus about the gold standard technique since there are several drawbacks and limitations inherent to each modality. Bone scintigraphy (BS) is sensitive for identifying the failed joint replacement, but cannot differentiate between infection and aseptic loosening. Combined bone/gallium scintigraphy (BS/GS) offers modest improvement over BS alone for diagnosing PJI. However, due to a number of drawbacks, BS/GS has generally been superseded by other techniques but it still may have a role in neutropenic patients. Radiolabelled leucocyte scintigraphy remains the gold standard technique for diagnosing neutrophil-mediated processes. It seems to be that combined in vitro labelled leucocyte/bone marrow scintigraphy (LS/BMS), with an accuracy of about 90%, is currently the imaging modality of choice for diagnosing PJI. There are, however, significant limitations using in vitro labelled leucocytes and considerable effort has been devoted to developing alternative radiotracers, such as radiolabelled HIGs, liposomes, antigranulocyte antibodies and fragments, as well as more investigational tracers such as radiolabelled antibiotics, antimicrobial peptides, bacteriophages and thymidine kinase. On the other hand, positron emission tomography (PET) is still growing in the field of PJI imaging with radiotracers such as (18)F-fluorodeoxyglucose (FDG), (18)F-FDG white blood cells and (18)F-fluoride. But unfortunately this superb tomographic technique will only receive full acceptance when specific PET uptake patterns can be successfully developed. The emergence of hybrid modality imaging using integrated single photon emission computed tomography (SPECT) and PET with computed tomography (SPECT/CT and PET/CT) may also have a contributing role for more accurate assessment of joint replacement complications, especially combined with new radiotracers such as (68)Ga and (64)Cu. Finally, in searching for infection-specific tracers, currently there is no such diagnostic agent available.