Antibiotic therapy in fracture-related infections (FRIs) can be challenging. FRIs are biofilm-related, so surgical debridement (and removal of the infected hardware, where possible) remains the mainstay of treatment together with prolonged antimicrobial therapy adapted to the causative microorganism and the patient, guided by a collaborative multidisciplinary team with expertise in this pathology. Optimal use of antimicrobial therapy should take into account many aspects like patient features (age, weight, underlying conditions, drug interactions, etc.), spectrum of activity, local resistance patterns, toxicity, and economic costs. In FRI, antibiotic posology should be optimized by using initial high-loading doses and prolonged infusions of molecules with time-dependent bactericidal activity, such as beta-lactams. Therapeutic drug monitoring should be used when available. In suspected FRIs, early, empirical broad-spectrum antibiotics that cover both Gram-positive and Gram-negative bacteria should be initiated (after sampling whenever possible). Once FRI is confirmed, targeted antimicrobial therapy, guided by the microorganism growth in cultured surgical samples, is essential in managing these infections effectively. Fluoroquinolones combined with rifampicin in susceptible bone infections are associated with higher infection eradication rates. The complexity of these infections, coupled with the emergence of antimicrobial multidrug resistance, underscores the need for innovative treatment strategies like new antimicrobial agents, long-acting lipoglycopeptide antibiotic agents or personalized bacteriophage therapy combined with antibiotics.