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The podocyte is a highly specialized cell, forming within the developing glomerulus from a mesenchymal origin, acquiring some but not complete features of an epithelial cell as it matures. Once mature, this cell has the potential to receive signals from several different directions and sits within a dynamic microenvironment. By taking an overview of many lines of evidence, it is clear that we already know many signals that are tightly controlled in keeping the podocyte healthy. For example, vascular endothelial growth factor, insulin and integrins are all known to have bidirectional effects on podocyte functionality, depending on whether there is too much or too little. It is of little surprise therefore that disrupting this delicate balance can result in a dramatic loss of function, and manifestation of glomerular disease originating from many different primary insults. The cues directing podocyte phenotype and functionality for the purpose of this review will be divided into four main sources: (i) genetic, (ii) paracrine signals from endothelial and mesangial cells, (iii) direct contact signals to/from the glomerular basement membrane and (iv) signals from circulating plasma. Of course there are other influences, which we still know little about, such as flow and shear stresses, signals from the urinary space that should all be considered in the overall healthy environment.