With more than 6,000 new pediatric patients with treatment-resistant nephrotic syndrome in the US each year alone, the unmet need for novel, podocyte-specific therapies is substantial. Recently, the established therapeutic benefit of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) was used as a starting point to gain insight into the pathomechanism of primary podocytopathies. A calcium (Ca²⁺)-mediated pathway has been identified that connects the angiotensin type 1 receptor (AT1R) to podocyte cytoskeletal dynamics, essential for a functioning glomerular filtration barrier. This discovery provided an important missing piece in our understanding of the pathomechanism of filter barrier damage, revealing Ca²⁺ signaling as critical for podocyte health and disease. The identification of the two Ca²⁺ permeant channels TRPC5 and TRPC6 as mediators of this pathway not only bolstered the importance of podocyte cytoskeleton dynamics but also revealed promising drug targets for treatment-resistant nephrotic syndrome. This review will focus on this novel signaling pathway in primary podocytopathies and its implications for next-generation therapies for glomerular disease.