© 2014 S. Karger AG, Basel. Background: Proteinuria is a cardinal sign of chronic kidney disease, which is a major healthcare problem that affects millions of people worldwide. Recent advances in molecular genetics and cell biology have revealed the podocyte as the primary functional regulator of the tri-layered glomerular filter. Since podocyte foot processes (FP) and their interposed slit diaphragms (SD) form the final barrier to protein loss, podocyte injury causes proteinuric kidney disease.Summary: A fundamental mechanism of proteinuric glomerular diseases is podocyte FP effacement and the loss of podocyte SD integrity, both of which involve the active rearrangement of the podocyte actin cytoskeleton. Initially, these early changes are reversible, but later can progress to cell detachment and death. Based on the importance of the actin cytoskeleton for podocyte development and the maintenance of the glomerular filter, podocyte research is heavily focused on studying actin's molecular make-up and regulation. In this review we provide a comprehensive summary of the about 100 actin-associated proteins that have been described in podocytes to date, and we point out that so far only about one quarter of them have been shown to be functionally relevant for podocyte function in rodents or humans. Since actin-mediated cell plasticity is a key feature of normal podocyte function, and alterations in actin dynamics appear to be a major driver in changing podocyte morphology and glomerular permeability, we discuss the current work on proteins and mechanisms that regulate actin polymerization and stress fiber contraction in podocyte FP in greater detail.Key Message: Without a doubt, the actin cytoskeleton is the key component of podocytes and proper glomerular filtration. Over the past 20 years many actin-associated proteins and actin-regulating mechanisms have been identified in podocytes. However, since most of these proteins are widely expressed and regulate actin in different cell types, it remains unclear if the podocyte actin cytoskeleton can be specifically targeted, and if and how actin-associated proteins can serve as novel drug targets in proteinuric kidney disease.