Alport syndrome is a progressive, hereditary disorder of basement membranes caused by variants in genes encoding the α3, α4, or α5 chains of type IV collagen (COL4A3, COL4A4, and COL4A5) leading to glomerulopathy, kidney failure, hearing loss, and eye abnormalities. The absence or dysfunction of the α3-α4-α5 (IV) heterotrimer triggers multiple compensatory and detrimental pathways within all layers of the glomerular filtration barrier. Developing a therapeutic strategy for patients with Alport syndrome depends on understanding these mechanisms of disease progression that are predominant at different times throughout the disease course. These strategies may include reconstitution of the α3-α4-α5 (IV) network in the glomerular basement membrane, reducing biomechanical strain and glomerular hyperfiltration, chaperone therapy, blocking aberrant signaling between the glomerular basement membrane and podocytes, reducing endothelial cell injury, reducing inflammation, and blocking fibrosis pathways.