Periprosthetic joint infections after total joint replacement such as total hip replacement or total knee replacement are a debilitating complication for patients that require multiple surgical interventions, long duration of antibiotics, and if failed may need a complete revision of the prosthetic implant. Debridement, antibiotics, and implant retention (DAIR) can be applied to treat the infection during an intervention, but reinfection rates remain high (25–40%). This is most probably related to inadequate bacterial removal at the implants interface, which is due to the “invisibility of these bacteria.” As such, the unmet clinical need to optimize this DAIR procedure can be addressed via incorporation of molecular imaging-based image guidance. In this manuscript, possibilities are described that can help provide image-guided technologies for image-guided DAIR, focussing on the treatment of bacterial infections that reside on prosthetic implants. Complementary modalities that can help guide innovative new treatment paradigms for prosthetic joint infections (PJI) are described, including hybrid chemical agents that can target bacteria, with focus on combined MRI optical/optoacoustic imaging and nuclear/optical imaging. Moreover, the implications of tracer pharmacokinetics after either systemic or topical tracer applications are addressed and innovative applications that become possible through image-guided DAIR therapy are discussed. In analogy to trends seen in surgical oncology, these innovations can potentially guide surgeons to focus the DAIR procedure toward areas of infection and support efforts that set out to improve the therapeutic efficacy of DAIR.