There is an urgent need to identify novel interventions for mitigating the progression of diabetic nephropathy. Diabetic nephropathy is characterized by progressive renal fibrosis, in which tubulointerstitial fibrosis has been shown to be the final common pathway of all forms of chronic progressive renal disease, including diabetic nephropathy. Therefore targeting the possible mechanisms that drive this process may provide novel therapeutics which allow the prevention and potentially retardation of the functional decline in diabetic nephropathy. Recently, the Ca 2+ -activated K + channel K Ca 3.1 (KCa3.1) has been suggested as a potential therapeutic target for nephropathy, based on its ability to regulate Ca 2+ entry into cells and modulate Ca 2+ -signalling processes. In the present review, we focus on the physiological role of K Ca 3.1 in those cells involved in the tubulointerstitial fibrosis, including proximal tubular cells, fibroblasts, inflammatory cells (T-cells and macrophages) and endothelial cells. Collectively these studies support further investigation into K Ca 3.1 as a therapeutic target in diabetic nephropathy.