Activated protein C (aPC) is the key effector protease of the natural protein C anticoagulant pathway and exerts anticoagulant, as well as anti-inflammatory activity. This dual mode of action has been thought to underlie the therapeutic efficacy of recombinant aPC in the treatment of patients suffering from severe forms of sepsis. The development and characterization of recombinant variants of aPC with altered bioactivity profiles has generated an opportunity to test this concept by dissecting the roles of aPC's anticoagulant and cell-signaling functions in the treatment of sepsis. Animal studies suggest that aPC variants with near-normal signaling function, but with greatly diminished anticoagulant potential may exhibit a substantially improved risk-to-benefit ratio in sepsis therapy.