The expression of antimicrobial peptides and proteins is an important innate immune defense mechanism that has recently been shown to be essential for cutaneous defense against invasive bacterial disease. Newborns have an immature cellular immune defense system that leads to increased susceptibility to infections. Here we show that skin from embryonic and newborn mice, as well as human newborn foreskin, express antimicrobial peptides of the cathelicidin and &bgr;-defensin gene families. Immunohistochemistry andin situhybridization demonstrated abundant cathelicidin protein and mRNA is present in normal skin during the perinatal period. Quantitative real-time PCR showed mouse cathelicidin expression (CRAMP) is 10- to 100-fold greater in the perinatal period than adult. Murine &bgr;-defensins-1 and -4 and human &bgr;-defensin-2 were also present in newborn skin. Combined, human cathelicidin (LL-37/hCAP/18) and &bgr;-defensin-2 demonstrated synergistic antimicrobial activity and efficiently killed group BStreptococcus, an important neonatal pathogen. Antimicrobial peptides may therefore provide a compensatory innate defense mechanism during development of cellular immune response mechanisms in the newborn period.