Severe illness of almost any form, including sepsis and septic shock, severe trauma, burns or other overwhelming stresses are characterized by an intravascular activation of the host’s inflammatory pathways releasing potent inflammatory mediators into the circulation [1]. Previous workers referred to this response as the systemic inflammatory response syndrome (SIRS)[2] to accentuate the nonspecific inflammatory nature of the process as assessed by measures of circulating active small molecules capable of inducing a generalized inflammatory response. Furthermore, if sustained, this system-wide inflammatory process may result in loss of the normal vasoregulatory adaptations to stress and metabolic demand. This peripheral vascular paralysis often precedes the development of multiple organ system dysfunction and death in critical illness. Historical perspectives, recent clinical trials of immunomodulating agents and cellular and molecular data have created an exciting and productive story that only recently led to the first positive outcome trial of pharmacotherapy for severe sepsis.