Focal segmental glomerulosclerosis (FSGS) is the most common primary glomerular disorder causing end-stage renal disease. Since the first description of this clinicopathological entity in the early 1930s, various studies have identified numerous underlying pathogenetic mechanisms. Nevertheless, FSGS is still a complex, only partially understood and in its classification sometimes confusing disease. A unifying pathophysiological concept has not been identified and might not even exist. However, research efforts of past decades identified FSGS as a podocytopathy with several podocyte molecules being key players in the development and the course of FSGS. Podocytes are crucially involved in the formation of the glomerular barrier and any assault on their delicate physiological balance and architecture can result in the development of proteinuria. The following review article will introduce most recent examples identifying novel players in the complex pathogenesis of FSGS.