The virulence of pathogenic bacteria is critically dependent on their ability to produce toxins that attack eukaryotic target cells. Microbial toxins are either structural components of the bacterial cell wall (endotoxins) or actively secreted proteins (exotoxins). Sepsis and septic shock, which represent major causes of mortality in modern intensive care medicine, are caused by an inadequate inflammatory and immunological host response to bacterial infection. Emerging evidence suggests that the systemic spread of microbial toxins, rather than bacteremia itself, is the crucial event in the pathogenesis of this dramatic dysregulation. The endothelium, with its diversity of physiological functions is a main target of bacterial toxins. The resulting endothelial dysfunction is believed to contribute to the underlying pathomechanisms and the collapse of homeostasis of organ function. In vitro, bacterial toxins induce subtle alterations of endothelial cell function rather than massive cell damage. Furthermore, bacterial toxins targeting endothelial cells severely alter the behavior of extravascular cells and circulating leukocytes via excessive formation of vasoactive mediators and overexpression of adhesion molecules. Research on the effects of microbial toxins on vascular endothelium has broadened our general understanding of microbial strategies to induce organ damage, even in the absence of viable bacteria. Combining antitoxin strategies with antibiotic therapy may prove to be of benefit to patients suffering from bacterial sepsis in the future.