The systemic inflammatory response that typifies septic shock can induce widespread tissue injury, endothelial dysfunction and lethality. Interventions that disrupt the systemic inflammatory response have been the central treatment strategy for septic shock for decades. In experimental models, inhibitors of generalized inflammation are of clear survival benefit when the inducing stimulus is LPS or other bacterial toxins. However, the response to inhibitors of inflammation in actual infection models such as pneumonia, peritonitis or soft tissue infections generate variable results with improvement in some animal models and harm in others. Intrinsic counter regulatory mechanisms that accompany systemic inflammation can induce a prolonged phase of relative immune suppression. Attempts to restore immune function by immunoadjuvants have become a potential therapy for sepsis. Genomic evidence indicates that activation of innate immunity and depression of adaptive immunity occurs simultaneously in the very early phases of septic shock. The magnitude of the change from resting state is the most predictive outcome rather than specific patterns of immune dysfunction. Non-resolving information poses a real challenge from a therapeutic prospective in patients with septic shock. A new generation of anti-inflammatory agents and anticoagulants are now in clinical development along with a variety of immunostimulants that promote adaptive immune function and inhibitors of negative regulators of inflammation such as programed cell death (PD-1) or B and T lymphocyte attenuator. These interventions are in clinical trials, and the results will determine the direction in which experimental therapeutics take in the near future in the management of septic shock.