Sepsis, a widely prevalent disease with increasing morbidity and mortality, is thought to result from uncontrolled inflammatory responses to microbial infection and/or components. However, failure of several experimental anti-inflammatory therapies has necessitated re-evaluation of the paradigm underlying the pathogenesis of this complex disorder. Apoptotic cell death forms a second dominant feature of septic shock in patients and animal models. Anti-apoptotic strategies may protect animals from septic death. However, simultaneous occurrence of apoptosis and inflammation is necessary for septic death. At the cellular level, apoptosis plays a central role in the development of the lymphoid system and regulation of immune responses. Immune activation renders cells refractory to apoptosis while apoptosis of activated lymphocytes is an important immunoregulatory mechanism. Factors such as complement factor 5a, caspase-1 and mitogen-activated protein kinase, which participate in apoptosis as well as pro-inflammatory pathways, may be responsible for simultaneous activation of apoptosis and inflammation in sepsis. Further identification of other similar biochemical events capable of co-activating inflammation and apoptosis may provide new targets for therapy of this hitherto untreatable disease.