Therapy for severe sepsis and septic shock remains a major unmet medical need and novel treatments to regulate the disordered inflammatory response in sepsis are needed if improved outcomes in sepsis are to be realized in the future. Current therapy is primarily supportive and includes timely administration of antibiotics, source control of infection, aggressive fluid resuscitation, organ support and use of activated protein C where clinically indicated. Bacterial mediators including endotoxin and superantigens as well endogenous proinflammatory cytokines are critical to the pathogenesis of sepsis-induced organ failure and are being targeted with numerous molecules and removal devices. Additional therapeutic strategies are focused at restoring the natural anticoagulant levels, blocking deleterious effects of the complement cascade, preserving mitochondrial function, and inhibiting excessive lymphocyte apoptosis. Molecules with pluripotent activity such as inter-alpha inhibitor proteins, sirtuin activators and estrogen-receptor ligands are also being investigated. Efforts are underway to re-establish microbial clearance mechanisms and permit immune reconstitution following sepsis-induced immune suppression. A review of the most current agents being investigated and their current status are presented in this chapter. The organization of this chapter includes sections addressing therapies targeting microbial mediators, including endotoxin, as well as therapies targeting inflammation and coagulation. There is also a section on agents targeting novel mediators and pathways.