This review examines neonatal bacterial skin infections with respect to host immunity, bacterial pathogens, patterns of infection, and new therapeutic approaches. Advances have been made in our understanding of innate host defense and the emerging role of cutaneous antimicrobial peptides of the cathelicidin and defensin families. Toll-like receptors are being investigated with respect to their interactions with bacteria and other components of the innate immune defense, such as the antimicrobial peptides. The epidermal barrier remains an active area of research. Studies confirm that maintaining an intact epidermal barrier by minimizing exposure to soap and by not removing vernix caseosa are simple measures to improve skin barrier function. Active barrier-enhancing measures such as the application of topical emollients have shown mixed results in the prevention of nosocomial infection. A meta-analysis of studies performed in developed countries showed a trend of increasing risk for coagulase-negative staphylococcal infection. By contrast, a randomized controlled trial showed that infants treated with sunflower oil are less likely to experience nosocomial infections than are control infants. Infants with bacteremia and no known source of infection should be carefully examined because cutaneous abscesses have been shown to be an important nidus of infection. Methicillin-resistant Staphylococcus aureus is reaching epidemic proportions, making surface cultures an essential part of the evaluation of cutaneous bacterial infection. New insights have been gained regarding the basic science of neonatal host defense and these advances may produce new ways of approaching the prevention and treatment of bacterial skin infections in the newborn period.