Human tissue kallikrein-binding protein (Kallistatin, KS) was first found to bind to tissue kallikrein (TK) and inhibit its function as a serine protease inhibitor (SERPIN). Recent studies found that KS has extensive biological effects including anti-inflammation, oxidation resistance, anti-angiogenesis and anti-tumor activities; its mechanism is closely related to its heparin-binding domain. KS can competitively inhibit TNF-α or HMGB1 binding to its corresponding endothelial cell surface receptor via its heparin-binding domain, thereby inhibiting expression of inflammatory cytokines mediated by TNF-α or HMGB1. KS can also competitively inhibit VEGF or bEGF binding to its receptor, thereby inhibiting VEGF or bEGF mediated tumor angiogenesis. KS plays a role in oxidative stress by involving in the regulation of several cell signaling pathways. KS can also regulate endothelial cell function and induce tumor cell apoptosis. With a variety of biological activities, KS has broad application prospects. Especially for multi-target therapy of disease such as sepsis, KS has potential therapeutic value. Its biological mechanism needs further research. In this paper, the latest research progress in biological effects and mechanism of KS will be elaborated.