The discovery of Toll-like receptors (TLRs) as essential components of the innate immune system has greatly advanced our knowledge and understanding of immune responses to infection and how these are regulated. Innate immunity in general and TLRs in particular play a crucial role in the front line of host defenses against microbes, but also are a key element in the proper functioning of the immune system at large in vertebrate animals. The innate immune system has been identified as a collection of factors, both cell-associated and cell-free, that comprises an impressively effective and well-organized system that is capable of immediate recognition of a whole array of microbes and microbial components. The cell-bound TLRs fulfill a central role in the process from pathogen recognition to activation of adaptive immunity. From the cell-free factors the plasma protein mannose-binding lectin (MBL) has been studied most extensively. Associations have already been documented between TLR polymorphisms in man and TLR deficiency in animals and an increased susceptibility to infection. The effect of MBL on infectious disease susceptibility only seems to emerge when host defenses are compromised by a severe underlying condition. The functional state of the various components of innate immunity at birth is largely unknown and only recently a number of studies have assessed this feature of the innate immune system. In addition, for the human newborn the innate immune system may have a broader significance; it may well be the key system determining the course of inflammatory events associated with premature birth, a notion that is emphasized by the recently described association between TLR polymorphisms and prematurity. However, there are still many open questions, particularly about the exact relation between individual TLRs and infectious disease susceptibility and how TLRs cooperate in resistance to infection and in initiating adaptive immune responses. With regard to the human newborn, the most relevant question that needs to be resolved is the precise role of innate immunity in the pathogenesis of prematurity.