Beta-lactam antibiotics, particularly penicillins and cephalosporins, are among the most frequently prescribed antimicrobial agents worldwide and represent the most common cause of immunologically mediated drug hypersensitivity reactions. Approximately 8%–15% of the population carries a penicillin allergy label, yet over 95% of these patients tolerate penicillins upon appropriate evaluation. The historical concern that penicillin-allergic patients have a 10% risk of cross-reactivity with cephalosporins originated from studies in the 1960s and 1970s involving first-generation cephalosporins contaminated with trace penicillin and has been substantially overestimated. Contemporary evidence demonstrates that cross-reactivity between penicillins and cephalosporins is primarily determined by structural similarity of R1 side chains rather than the shared beta-lactam ring. Cefazolin possesses a unique R1 side chain not shared with any other beta-lactam, while second-, third-, and fourth-generation cephalosporins have progressively more complex R1 structures lacking homology with penicillins, resulting in negligible cross-reactivity. Large‑scale studies demonstrate that later‑generation cephalosporins, particularly cefazolin with a dissimilar R1 side chain, are associated with very low reaction rates in patients with a penicillin allergy label, including carefully selected individuals with a history suggestive of anaphylaxis, when used within structured risk‑stratification protocols and in accordance with institutional guidelines. However, in patients with documented severe immediate hypersensitivity reactions, decisions regarding cephalosporin use should remain individualized, taking into account the suspected culprit drug, side‑chain similarity, the availability of allergy specialist consultation, and local protocols. Avoidance of cephalosporins in penicillin-allergic patients leads to increased use of alternative antibiotics such as clindamycin and vancomycin, which are associated with 50% higher odds of surgical site infections, increased adverse events, and higher healthcare costs. Risk stratification tools based on index reaction characteristics enable safe cephalosporin use in the majority of patients without routine skin testing. Knowledge gaps persist among healthcare professionals, highlighting the need for ongoing education to translate current evidence into clinical practice.