Sepsis, manifested by systemic inflammatory response syndrome (SIRS), septic shock and multiple organ dysfunction syndrome (MODS), remains the leading cause of morbidity and mortality in critically ill patients. Despite advances and our knowledge of sepsis, there remain clinical dilemmas that impact how we treat patients. These clinical dilemmas include hypotension, cardiac dysfunction and altered oxygen consumption. There is increasing recognition that treatment of these problems does not necessarily improve outcome. As we improve our understanding of sepsis, there is increased recognition that improvement in morbidity and survival will come not only from treating the manifestations of sepsis but also the endogenous mediators responsible for the development of these clinically important conditions. This manuscript discusses the clinical dilemmas associated with sepsis, current therapy and future directions for managing sepsis.