AVIL (advillin) is a calcium-regulated actin-binding protein primarily functioning in cytoskeletal organization and cell morphogenesis. It regulates actin bundling and filopodia formation in fibroblasts, controls lamellipodia assembly in podocytes through PLCE1 and ARP2/3 complex regulation, and plays critical roles in neuronal development, axon regeneration, and ciliogenesis. In podocytes, AVIL modulates EGF-induced diacylglycerol generation to regulate lamellipodium formation 1. Clinically, AVIL dysregulation is most significant in rhabdomyosarcoma (RMS), the most common pediatric soft-tissue malignancy. AVIL acts as a bona fide oncogene in RMS through multiple mechanisms: it forms oncogenic MARS-AVIL fusion proteins via chr12 inversion, undergoes locus amplification, and is frequently overexpressed in RMS cell lines, patient-derived xenografts, and both alveolar and embryonal RMS subtypes 2. RMS cells exhibit oncogene addiction to AVIL activity, with silencing nearly eradicating cells in culture and inhibiting xenograft growth, while AVIL overexpression transforms mesenchymal stem cells in vitro and in vivo 2. AVIL functions as a converging node upstream of PAX3-FOXO1 and RAS pathways, connecting different RMS subtypes 2. AVIL overexpression correlates with worse clinical prognosis and occurs in other sarcomas 2, making it a potential therapeutic target despite the historical challenges in drugging actin-binding proteins 3. AVIL mutations also associate with nephrotic syndrome 21.