In recent years, extensive basic science research has led to a clear understanding of the molecular mechanisms contributing to the pathophysiology of sepsis. Sepsis is now defined as a systemic inflammatory response syndrome (SIRS) in which there is an identifiable focus of infection. SIRS can be also precipitated by non-infective events such as trauma, pancreatitis, and surgery. As a consequence of an overactive SIRS response, the function of various organ systems may be compromised, resulting in multiple organ dysfunction syndrome (MODS) and death. Production and activation of multiple proinflammatory genes are likely to play a key role in the pathogenesis of MODS development. This review article focuses on the molecular mechanisms and components involved in the pathogenesis of severe sepsis. This includes cellular targets of sepsis-inducing bacterial products and their signaling pathways with a major emphasis on transcription factors and new therapeutic approaches to severe sepsis.