In contrast to most glomerular diseases, the injury pattern in focal segmental glomerulosclerosis (FSGS) is highly heterogeneous, even though podocytes are genetically identical and exposed to the same environmental factors. To understand changes in individual podocytes, we generated and analyzed a stochastic multicolor Cre-reporter, encoding four fluorescent proteins. In these animals, podocytes were randomly labeled allowing individual cells and their foot processes to be distinguished. In healthy animals, podocyte size and structure showed little cell to cell variability. In the doxorubicin-induced FSGS model, fluorescent-labeled glomerular podocyte numbers decreased and fluorescent cells could be recovered from the urine. The size of the remaining podocytes showed a high degree of heterogeneity, some cells remained small, while others enlarged. Both enlarged and non-enlarged podocytes showed alterations in their foot process morphology. Thus, by the virtue of a multicolor cre-reporter, individual podocytes could be viewed in real time at a cellular resolution indicating a heterogeneous podocyte injury response during the pathogenesis of FSGS.