Exposure of blood to a variety of artificial surface induces contact activation, a process that contributes to the host innate response to foreign substances. On the foreign surface, the contact factors, factor XII (FXII), and plasma prekallikrein undergo reciprocal conversion to their fully active protease forms (FXIIa and α-kallikrein, respectively) by a process supported by the cofactor high-molecular-weight kininogen. Contact activation can trigger blood coagulation by conversion of factor XI (FXI) to the protease FXIa. There is interest in developing therapeutic inhibitors to FXIa and FXIIa because these activated factors can contribute to thrombosis in certain situations. Drugs targeting these proteases may be particularly effective in thrombosis triggered by exposure of blood to the surfaces of implantable medical devices. Here, we review clinical data supporting roles for FXII and FXI in thrombosis induced by medical devices, and preclinical data suggesting that therapeutic targeting of these proteins may limit surface-induced thrombosis.