Severe sepsis and septic shock are common in the critically ill patient and account for considerable morbidity and mortality not to mention the high associated costs. Advances in our understanding of sepsis pathophysiology and in the important link between the inflammatory response to sepsis and activation of coagulation led to the development and licensing of the first ever, specific, immunomodulatory anti-sepsis drug. Drotrecogin alfa (activated), a recombinant version of activated protein C, was shown in a large randomized controlled clinical trial to reduce mortality rates from 30.8% in the placebo group to 24.7% in the treatment group, which equated to one additional life saved for every 16 patients treated. Vasopressor requirements and duration of mechanical ventilation were also reduced. Apart from an expected increased risk of severe bleeding, mostly associated with interventions, drotrecogin alfa (activated) was not associated with any other adverse reactions. In this article, I will briefly summarize the events leading to the development of drotrecogin alfa (activated) including aspects of sepsis epidemiology and pathophysiology and the results of early animal and clinical studies. The results of the large multicenter phase III PROWESS study will then be reviewed, along with results from subsequent open-label studies. Finally, I will focus on the key side effect issue with drotrecogin alfa (activated), that of increased bleeding, drawing data from the available clinical studies, and highlighting the contraindications and precautions when prescribing this drug.