Sepsis and resulting multiple system organ failure are the leading causes of mortality in intensive care units. Although it is generally appreciated that rampant, deregulated inflammatory pathways play a major role in sepsis, a comprehensive understanding based on the integrated response of multiple signal transduction pathways has remained elusive. Here we review the main signal transduction pathways involved in the progression from inflammation to sepsis and discuss emerging genomic, proteomic, and systems biology approaches to decipher how these signaling pathways converge to cause the septic state. We propose that an integrative approach involving functional proteomics will provide a quantitative and mechanistic description that unifies inflammatory signaling networks in sepsis and will identify critical regulatory nodes for therapeutic manipulation. These types of systems biology-based approaches may lead to more effective therapies than those currently available.