Regulation of fibrinolytic activity can be achieved by several mechanisms, ranging from regulating the production and localization of the plasminogen activators and their inhibitors, the degradation and inactivation of plasmin via autoproteolysis, and the synthesis and localization of the cell surface receptors for plasminogen. Binding of the inactive zymogen plasminogen to its cell surface receptors has been shown to significantly increase the rate of its conversion to the active serine-protease plasmin by co-localizing plasminogen with its activators, the tissue-type plasminogen activator (tPA) and the urokinase-type plasminogen activator (uPA) [1–3].One such cell surface plasminogen receptor is S100A10 (p11) [4]. S100A10, a member of the S100 protein family, was initially discovered as an annexin A2 (p36) binding partner [5–7]. S100A10 has also been found to interact with other cellular proteins including the Rho GTPase-activating protein DLC1 [8], cytosolic phospholipase A2 [9], the serotonin 1B receptor [10] and various ion channels, including the potassium channel TASK-1 [11], the sodium channel Na(V)1.8 [12] and the calcium channels TRPV5 and TRPV6 [13]. However, the major binding partners of S100A10 on the cell surface are tPA and plasminogen [14]. The focus of this review will be to discuss the role that extracellular S100A10 plays in regulating the conversion of plasminogen to plasmin and the physiological consequences of that process (Figure 1).