Numerous studies over the last two decades revealed a complexity and multiple functions of tissue transglutaminase (tTG or TG2, EC 2.3.2.13). Besides the ability to catalyze Ca2+-dependent transamidation of proteins and formation of protein polymers via protease-resistant covalent isopeptide bonds, tTG also possesses GTPase enzymatic activity which links this protein to certain intracellular signaling pathways. Moreover, in addition to cytoplasmic and nuclear localization, a significant part of the protein pool is present on the cell surface. A number of recent findings indicate that surface tTG is involved in the interactions of cells with the surrounding extracellular matrix (ECM). In this review we will focus on the newly defined non-enzymatic adhesive function of tTG in cell-matrix interactions and discuss contributions of previously characterized enzymatic activities of tTG to cell-matrix adhesion and adhesion-dependent processes. Understanding molecular interactions and enzymatic activities of tTG will gain further insights into the role of this protein in normal human physiology and various pathological conditions.