Fracture-related infections (FRIs) pose a significant challenge in orthopedic trauma care. Surgical treatment is based on sampling, debridement, and removal of any foreign bodies, management of dead space and soft tissues, and postoperative targeted antibiotic therapy. In cases of FRI in a healed fracture (F1 in the FRI classification), treatment mainly consists of debridement and hardware removal, if implants are present, followed by antibiotic therapy. Debridement, antibiotics, and implant retention (DAIR) is mainly indicated in F2 cases with good soft tissue coverage (I1–I3), if adequate debridement is possible. Retention of intramedullary nails in F2 is most likely associated to a higher rate of treatment failure due to their inaccessible intramedullary parts, compromising the quality of the debridement. Therefore, their exchange is recommended even in F2 situations. For F3 cases, implant exchange is mostly required as bone healing will most likely not progress. External fixation should be considered in patients with relevant comorbidities (R4) and/or poor immune status, as well as in those with critical soft tissue situations.