Spleen tyrosine kinase (Syk), a 72 kDa cytoplasmic non-receptor protein-tyrosine kinase, plays an important role in signal transduction in a variety of cell types. Ever since its discovery in the early 1990s, there has been accumulating evidence to suggest a pathogenic role of Syk in various allergic disorders, autoimmune diseases and malignancies. Additionally, there is emerging data from both pre-clinical and clinical studies that Syk is implicated in the pathogenesis of proliferative glomerulonephritis, including anti-glomerular basement membrane (anti-GBM) disease, ANCA-associated glomerulonephritis (AAGN), lupus nephritis (LN), and immunoglobulin A nephropathy (IgAN). Moreover, recent animal studies have shed light on the importance of Syk in mediating acute renal allograft rejection, Epstein Barr virus (EBV)-associated post-transplant lymphoproliferative disease (PTLD) and kidney fibrosis. Fostamatinib, an oral Syk inhibitor, has undergone clinical testing in rheumatoid arthritis (RA), refractory immune thrombocytopenic purpura (ITP), leukemia, and lymphoma. The recent STOP-IgAN trial showed that the addition of non-selective immunosuppressive therapy to intensive supportive care did not improve clinical outcomes in high-risk IgAN patients. A Syk-targeted approach may be beneficial and is currently being evaluated in a phase II randomized controlled trial. In this review, we will discuss the pathogenic role of Syk and potential use of Syk inhibitor in a variety of renal diseases.