Remodeling of extracellular matrix (ECM) is a key event in progression and reversal of kidney disease. This process results from synthesis of ECM components and their degradation, mostly by matrix metalloproteinases (MMPs). However, because of both the multiplicity of their targets that include non-matrix substrates, and the complexity of their regulation, MMPs may exert different, and even opposite, effects during the different phases of the evolution of kidney diseases. The major challenge with future therapeutic interventions will be to accomplish temporal control of MMP activity. In addition to MMPs, enzymes that stabilize ECM (transglutaminase) and cell receptors for ECM components including integrins and discoidin domain receptor-1 (DDR1), play an important role in the cell response to matrix remodeling. Novel therapeutic approaches aimed at targeting transglutaminase and ECM receptors, particularly DDR1, are a promising option provided that specific and safe pharmacological inhibitors be developed. These therapies together with pharmacological agents controlling MMP activity, given in appropriate windows of the course of kidney diseases may represent a useful adjunct to blockers of the renin-angiotensin system.