Sepsis is a medical emergency caused by a dysregulated host response to bacterial and viral infections. Current investigations reveal that each host can have a different and potentially unique response to a particular pathogen. These complex responses are typically via the immune system, but also include time-dependent alterations in organ function that change as the infection progresses, which can ultimately lead to septic shock and, in many patients, death. Apolipoprotein E is the most unique gene associated with sepsis. The single copy APOE-gene is uniquely polymorphic in humans causing humans to be the only species to express multiple ApoE-protein isoforms from a single gene. Since APOE-genotype differentially controls immune responses, several studies discussed below find that APOE4 carriers are at a significantly increased risk of death from sepsis compared to APOE3 carriers. In sepsis, RNA expression from APOE genes is reduced while circulating levels of ApoE-protein are significantly increased. The mechanism of this response has been attributed to a sepsis-mediated reduction of expression of receptors that bind ApoE-proteins thereby permitting increased circulating ApoE-protein levels. In addition to the protective effects of APOE3 genes, small peptide mimetics of the holo-ApoE protein have also been shown to protect against inflammation and death in animal models of sepsis. These data point to the potential of incorporating host APOE gene isotypes, expression of ApoE protein isoforms, and ApoE-mimetics to identify and reduce sepsis in the clinic and improve survival in sepsis patients.