Purpose of review Coagulase-negative staphylococci have emerged as the most common nosocomial pathogen in neonatal intensive care units worldwide. Our understanding of the interactions between coagulase-negative staphylococci and the immune system is incomplete, especially in the newborn. This review summarizes current knowledge on the human immune response to coagulase-negative staphylococci, with particular emphasis on the neonatal innate immune system.Recent findings There are very limited data on innate immune responses to coagulase-negative staphylococci in neonates. Levels of serum proteins, including transplacental anti-coagulase-negative staphylococci immunoglobulin and complement, correlate with gestational age, and this relative deficiency in preterm infants contributes to their suboptimal opsonization and impaired bacterial killing of coag u lase- negative staphylococci. In adults, coagulase-negative staphylococci elicit significant cytokine responses in vitro, which are probably partly mediated by Toll-like receptors, including Toll-like receptor type 2, but these pathways have not been characterized in the high-risk neonatal population.Summary The susceptibility of human preterm neonates to coagulase-negative staphylococci relates partly to the immaturity of the neonatal immune response. Strategies to reduce the burden of coagu lase- negative staphylococci infections require a thorough understanding of host-pathogen interactions, particularly the engagement of coagulase-negative staphylococci by the neonatal innate immune system.