A progressive increase in the incidence of infections caused by multidrug-resistant microorganisms is being reported. Among these resistant microorganisms, the main threats are extended-spectrum β-lactamase-, AmpC-, and carbapenemase-producing Gram-negative bacilli, methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. To address this important problem, it is essential to establish pediatric Antimicrobial Stewardship programs, perform active epidemiological surveillance and develop an adequate infection control policy. The therapeutic approach of these infections is often complex, frequently requiring antibiotics with less experience in children. In this position document made by the Spanish Association of Pediatrics and the Spanish Society of Pediatric Infectious Diseases, the epidemiology and treatment of these infections are reviewed according to the best available evidence.