Membrane type 1-matrix metalloproteinase (MT1-MMP) functions as a signaling molecules in addition to a transmembrane metalloprotease, which degrades interstitial collagens and extracellular matrix components. This review focuses on the multifunctional roles of MT1-MMP as a signaling molecule in vascular responses to pro-atherosclerotic stimuli in the pathogenesis of cardiovascular diseases. First, the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1)-MT1-MMP signaling axis contributes to endothelial dysfunction, which is mediated via small GTP-binding protein RhoA and Rac1 activation. Second, MT1-MMP plays a crucial role in reactive oxygen species (ROS) generation through the activation of receptor for advanced glycation end products (AGEs) in smooth muscle cells, indicating that MT1-MMP may be a therapeutic target for diabetic vascular complications. Third, MT1-MMP is involved in RhoA/Rac1 activation and Ca²⁺ signaling in the mechanism of thrombin-stimulated endothelial dysfunction and oxidant stress. Fourth, the inhibition of the MT1-MMP/Akt signaling pathway may be an attractive strategy for treating endothelial disordered hemostasis in the development of vascular diseases linked to TNF-α-induced inflammation. Fifth, MT1-MMP through RAGE induced RhoA/Rac1 activation and tissue factor protein upregulation through NF-κB phosphorylation in endothelial cells stimulated by high-mobility group box-1, which plays a key role in the systemic inflammation. These findings suggest that the MT1-MMP-mediated signaling axis may be a promising target for treating atherosclerosis and subsequent cardiovascular diseases.