Tissue-type plasminogen activator (tPA) is traditionally viewed as a simple serine protease whose main function is to convert plasminogen into biologically active plasmin. As a protease, tPA plays a crucial role in regulating blood fibrinolysis, in maintaining the homeostasis of extracellular matrix and in modulating the post-translational activation of growth factors. However, emerging evidence indicates that tPA also functions as a cytokine that transmits its signal across the cell membrane, initiates a diverse array of intracellular signaling, and dictates gene expression in the nuclei. tPA binds to the cell membrane LDL receptor-related protein 1 (LRP-1), triggers its tyrosine phosphorylation. As a cytokine, tPA plays a pivotal role in the pathogenesis of renal interstitial fibrosis through diverse mechanisms. It facilitates tubular epithelial to mesenchymal transition, potentiates myofibroblast activation, and protects renal interstitial fibroblasts/myofibroblasts from apoptosis. Together, growing evidence has implicated tPA as a fibrogenic cytokine that promotes the progression of kidney diseases. These new findings have radically changed our conception of tPA in renal fibrogenesis and represent a paradigm shift towards uncovering its cytokine function.