The extracellular matrix (ECM) is a complex and dynamic cross-linked protein network that supports organ integrity and homeostasis through modulation of cellular functions within the organ and mediates crosstalk towards environmental stimuli. The dysregulated extracellular matrix is the hallmark of kidney injury, inflammation, and fibrosis. With the recent development of advanced proteomics, genetics, genomics, and epigenomics, studies of the interplay between ECM components and cellular and molecular mechanisms in kidney health and disease, particularly during the repair stage of kidney injury and fibrosis, are emerging. Better characterization of kidney matrisome proteins and their functions for organ cross-communication, in combination with stem cell treatment and novel extracellular vesicle delivery platform, will benefit not only biomarkers identification but also target therapeutics development. All these exciting advances will build new regenerative medicine to eradicate chronic kidney disease.