Sepsis and septic shock are common problems in the ICU and carry a very high mortality. Myocardial depression is a common finding in patients with sepsis, and is usually reversible as the patient recovers. Both exogenous mediators, such as endotoxin, and endogenous cytokines, including tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6, have been implicated as important factors in the pathophysiology of septic shock and the development of myocardial depression in sepsis. Nitric oxide has also been implicated in the pathophysiology of the cardiovascular response to sepsis. Better understanding of the roles and interactions of these substances will be necessary to develop more effective therapies without increasing morbidity and mortality.