Much of the basic biochemistry of antiplasmin was described more than 20 years ago and yet it remains an enigmatic member of the serine protease inhibitor (serpin) family. It possesses all of the characteristics of other inhibitory serpins but in addition it has unique N- and C-terminal extensions which significantly modify its activities. The N-terminus serves as a substrate for Factor XIIIa leading to crosslinking and incorporation of antiplasmin into a clot as it is formed. Although free antiplasmin is an excellent inhibitor of plasmin, the fibrin bound form of the serpin appears to be the major regulator of clot lysis. The C-terminal portion of antiplasmin is highly conserved between species and contains several charged amino acids including four lysines with one of these at the C-terminus. This portion of the molecule mediates the initial interaction with plasmin and is a key component of antiplasmin's rapid and efficient inhibitory mechanism. Studies of mice with targeted deletion of antiplasmin have confirmed its importance as a major regulator of fibrinolysis and re-emphasized its value as a potential therapeutic target.