Abstract: Methods of treatment of sepsis are disclosed. These methods comprise administering to a subject a composition comprising at least one siRNA directed against at least one gene encoding a pro-apoptotic polypeptide. The pro-apoptotic polypeptide, in some aspects, can be other than Fas or caspase-8. In some embodiments, an siRNA can be directed against a pro-apoptotic component of the mitochondrial pathway, such as a pro-apoptotic bcl-2 protein. In some aspects, an siRNA can be directed against a BH3-only bcl-2 protein, while in other aspects, siRNAs can be directed against multi BH domain Bcl-2 family members such as bax and bak. In some embodiments, an siRNA can be directed against a death receptor pathway molecule such as FADD. In various configurations, a composition can also comprise a cationic lipid such as DOTAP, or nanoparticles comprising a cyclodextrin-containing polycation and a polymer such as a poly(ethylene glycol).