Sepsis is defined as the systemic inflammatory response of the human host that is triggered by an invading pathogen. Despite tremendous advances in both our knowledge of and treatment strategies for this syndrome, sepsis remains among the major causes of morbidity and mortality in children worldwide. Thus, we hypothesize that an improved mechanistic understanding obtained via basic and translational science will continue to identify novel therapeutic targets and approaches. As a result, given the central importance of the alterations in gene expression in regulating the human host's physiologic response to a pathogen, we review the complex factors-genetics, transcriptional expression, and epigenetics-that regulate unique gene-expression patterns in pediatric sepsis and septic shock. We anticipate that emerging data from genetic, genomic, and other translation studies in pediatric sepsis will advance our biological understanding of this response and undoubtedly identify targets for newer therapies.