Purpose of Review <p> Approximately 10% of the US population carries a penicillin allergy label (PAL), which complicates the prevention and treatment of bone and joint infections (BJIs). However, many patients with unassessed PALs can tolerate beta-lactam antibiotics. This review assesses the impact of PALs on BJIs, outlines penicillin de-labeling methods, and summarizes the antibiotic selection recommendations for prevention and treatment of BJI for confirmed PAL. </p> Recent Findings <p> PALs have been associated with higher rates of surgical site infections and mortality, longer hospitalizations, increased risk of ICU admission, and higher incidence of <i>Clostridioides difficile</i>, methicillin-resistant <i>Staphylococcus aureus</i>, and vancomycin-resistant <i>Enterococcus</i> infections. Studies show that up to 90% of patients with a PAL can tolerate penicillin when challenged and highlight the safety and cost-effectiveness of penicillin de-labeling protocols implemented preoperatively or during BJI treatment. </p> Summary <p> Unassessed PALs lead to unnecessary avoidance of first-line beta-lactam surgical prophylaxis, which is associated with increased surgical site infections and periprosthetic joint infections. They also complicate BJI treatment and result in the usage of antimicrobial agents with greater risk of toxicity and side effects. Current consensus supports implementing penicillin allergy evaluation and assessment protocols to increase the utilization of first-line beta-lactam agents. </p>