All species require a rapid, systemic reply to pathogens in their environment. This response is known as the innate immune response and is characterized by de novo synthesis of mediators that directly or indirectly through phagocytosis remove and kill the pathogen. Innate immune responses have been preserved throughout evolution and have been studied in detail in organisms from the fruit fly Drosophila melanogaster to humans. In my laboratory, studies performed during the past 25 yr have focused on defining the molecular basis of innate immune responses to microbial pathogens. Specifically, we have used bacterial endotoxin (lipopolysaccharide) as a model stimulus to define how the innate immune system recognizes products of microbial pathogens and initiates responses to remove and/or kill such organisms. Such studies also serve as models to understand more fully the mechanisms underlying a serious human disease known as septic shock. This article discusses septic shock and its relationship to innate immunity.