The choice of antibiotics for serious Gram-negative bacterial infections in the newborn must balance delivery of effective antibiotics to the site(s) of infection with the need to minimize selection of antibiotic resistance. To reduce the risk of selective pressure from large-scale cephalosporin usage, a penicillin-aminoglycoside combination is recommended as empiric therapy for neonatal sepsis. Where Gram-negative sepsis is strongly suspected or proven, a third-generation cephalosporin should ordinarily replace penicillin. Piperacillin-tazobactam can provide better Gram-negative cover than penicillin-aminoglycoside combinations, without the risk of selecting antibiotic resistance seen with cephalosporins, but further clinical studies are required before this approach to empiric therapy can be recommended. For antibiotic-resistant infections, a carbapenem remains the mainstay of treatment. However, rapid emergence and spread of resistance to these antibiotics means that in the future, neonatologists may have to rely on antibiotics such as colistin, whose pharmacokinetics, safety, and clinical efficacy in neonates are not well-defined.