Genetic studies of hereditary forms of nephrotic syndrome have identified several proteins that are involved in regulating the permselective properties of the glomerular filtration system. Further extensive research has elucidated the complex molecular basis of the glomerular filtration barrier and clearly established the pivotal role of podocytes in the pathophysiology of glomerular diseases. Podocyte architecture is centred on focal adhesions and slit diaphragms — multiprotein signalling hubs that regulate cell morphology and function. A highly interconnected actin cytoskeleton enables podocytes to adapt in order to accommodate environmental changes and maintain an intact glomerular filtration barrier. Actin-based endocytosis has now emerged as a regulator of podocyte integrity, providing an impetus for understanding the precise mechanisms that underlie the steady-state control of focal adhesion and slit diaphragm components. This Review outlines the role of actin dynamics and endocytosis in podocyte biology, and discusses how molecular heterogeneity in glomerular disorders could be exploited to deliver more rational therapeutic interventions, paving the way for targeted medicine in nephrology.