IgA nephropathy, the most common glomerulonephritis worldwide and an important cause of renal failure, is an autoimmune glomerulonephritis wherein immune complexes consisting of IgA1 with galactose-deficient O-glycans (autoantigen) and anti-glycan autoantibodies deposit in glomeruli. IgA nephropathy frequently manifests initially in adolescents and young adults. Macroscopic hematuria coinciding with mucosal infections of the upper respiratory tract and/or digestive system is a characteristic presentation. Accumulated data suggest a multi-hit pathogenetic pathway, in which galactose-deficient IgA1 is produced at elevated levels (hit 1) and is recognized by unique circulating autoantibodies (hit 2). This process promotes formation of nephritogenic immune complexes (hit 3) that deposit in the kidney, activate mesangial cells, and cause renal injury (hit 4). Mesangial cells proliferate and overproduce extracellular matrix proteins and cytokines, which may injure podocytes and induce proteinuria. Most of these pathogenetic steps are likely affected by multiple environmental and genetic factors, some of them associated with abnormal mucosal immune responses.