Research into the optimal antibiotic management of musculoskeletal infections has advanced tremendously over the past quarter century, including over a dozen randomized controlled trials and numerous observational studies. This review examines the rationale for and evidence base supporting modern approaches to antibiotic decision making and stewardship in orthopedic infections. Specific practice advances discussed include the increased and earlier use of oral antibiotics, other principles of antibiotic selection (eg, the notion of “bone penetration” and novel local antimicrobial strategies), individualizing durations of therapy, and increasingly selective approaches to empiric antipseudomonal therapy, suppressive antibiotic therapy, and periprocedural antimicrobial prophylaxis following arthroplasty.