This overview summarizes selected major developments over the last 40 years in understanding podocyte biology and its involvement in glomerular disease subjectively from my perspective. Serendipity has played a major role in my contributions to investigative nephrology that range from basic mechanisms of immune deposit formation in experimental membranous nephropathy to the role of a microRNA in FSGS. This review emphasizes the importance of continuous reality checks of experimental results obtained in vitro or with genetically modified animals with human disease.