Despite extensive research, bacterial sepsis and its associated systemic inflammation remain a major cause of morbidity and mortality in the pediatric intensive care unit. Advances in molecular biology, however, have improved our understanding of this disease process and have opened up new avenues of potential therapeutic approaches. One such exciting area has been the substantial and still growing evidence that the mammalian immune system uses a family of Toll-like receptors (TLRs) to generate a response to molecular patterns present on invading microorganisms. In particular, TLR4 is part of a recognition complex for bacterial lipopolysaccharide (LPS), thus raising the likelihood of its involvement in the inflammatory response to bacterial sepsis. This review highlights our understanding of the molecular biology of these receptors, focusing on the LPS response, and concluding with a summary of ongoing evaluation and potential therapeutic strategies for treating sepsis through blockade of TLR signaling.