Cephalosporins are among the most widely prescribed antibiotics in pediatric practice. However, their overuse - particularly third‑generation agents – has accelerated antimicrobial resistance (AMR) and raised concerns about long‑term safety. Objective. To synthesize contemporary (2024–2025) evidence on cephalosporin resistance epidemiology, prescribing patterns, clinical effectiveness, and safety in children, with emphasis on rational use strategies. Methods. A systematic literature search was conducted in PubMed, Scopus, and the WHO GLASS portal for studies published between 1 January 2024 and 1 February 2026. Only original research, meta‑analyses, and official reports with verified data were included. Results. The WHO GLASS 2025 report indicates that 16.7% of pediatric bacterial infections globally are resistant to first‑line antibiotics, with rates reaching 33% in South‑East Asia and the Eastern Mediterranean [1]. In Oceania, third‑generation cephalosporin resistance (G3CR) among Enterobacterales rose from 19% to 22% over five years [2]. A Turkish study documented 45.3% cefixime resistance in pediatric E. coli urinary isolates [3]. Paradoxically, Israel reported improved susceptibility to first‑generation cephalosporins (73%→82%) alongside increased fluoroquinolone resistance [4]. A meta‑analysis of 17 trials (n=155,944) confirmed that short courses (≤6 days) of β‑lactams, including cephalosporins, are non‑inferior to longer courses (>7 days) for community‑acquired pneumonia in children, with fewer serious adverse events [5]. In Kenyan neonatal units, third‑generation cephalosporin use varied from 0% to 100% across centers, reflecting an absence of standardized protocols [6]. The 2024 amoxicillin shortage in Europe led to a twofold increase in third‑generation cephalosporin prescribing [7]. In November 2024, the FDA expanded pediatric indications for ceftaroline to include complicated skin infections from 34 weeks’ gestational age and community‑acquired pneumonia from 2 months of age [8]. Conclusion. The effectiveness of empirical cephalosporin therapy in children is increasingly compromised by resistance and inappropriate use. Rational prescribing – guided by local susceptibility data, short‑course regimens, and stewardship programs – is urgently needed to preserve this vital antibiotic class.