Projections indicate an increase in primary and revision total joint arthroplasties (TJAs). Periprosthetic joint infections (PJIs) are one of the most common and devastating causes of failure after TJA. Perioperative administration of systemic and/or local antibiotics is used for both prophylaxis and treatment of PJI. Antibiotic stewardship is a term that has been met with clinical acceptance and success in other specialties of medicine. Identifying antibiotic best practice use in the fight against PJI is limited by studies that are extremely heterogeneous in their design. Variations in studies include antibiotic selection and duration, surgical débridement steps, type of antibiotic delivery (intra-articular, local, intravenous, and prolonged oral), mix of primary and revision surgery cohorts, both hip and knee cohorts, infecting organisms, and definitions of treatment success/failure. This review highlights the current challenges of antibiotic stewardship in TJA.