In diseases resulting in proteinuria, the delicate architecture of the podocyte is remodelled in response to as yet unknown signals. Crucial to understanding this has been the discovery of podocyte molecules that are mutated in hereditary proteinuric diseases, and which are functionally linked to the actin cytoskeleton. These molecules include nephrin, podocin and TRPC6, which are localised to the podocyte slit diaphragm. It is becoming increasingly clear that the slit diaphragm is a signalling complex, crucial to morphological integrity, though regulation of this process is little understood. A number of observations suggest that the podocyte response to external ligands is unique. For example TRPC6 is a widely expressed cation channel, yet activating mutations only affect the glomerulus(Winn et al. 2005). In clinical practice, nephrotic syndromes such as FSGS are thought to be caused by circulating plasma ‘factors’ that are directly toxic to the podocyte. We have shown that the circulating plasma protease, hemopexin, causes dramatic remodelling of the podocyte actin cytoskeleton, but has no effect on glomerular endothelial cells or fibroblasts. The slit diaphragm podocyte protein nephrin is restricted mainly to the podocyte, and recent data show that nephrin specifically signals to the actin cytoskeleton via the adaptor protein Nck(Jones et al. 2006). Our own studies now show that human plasma affects the podocyte in a unique way, affecting signalling to the actin cytoskeleton, subcellular localisation of nephrin and TRPC6 activation(Coward et al. 2005). These effects are dependent on the presence of nephrin, and we have evidence of a unique, nephrin-dependent, functionality of TRPC6 which switches this molecule between a plasma membrane ion channel and an intracellular calcium release channel. Additionally, the hemopexin effect is also dependent on nephrin. Therefore we consider that nephrin is a central player in slit diaphragm signalling, and confers specificity to the way the podocyte responds to external ligands in health and disease.