By functional genomics, we demonstrated that nearly all reported HNSCC-associated RAC1 aberrations, including gene copy increases, and the HNSCC-prevalent RAC1-A159V mutation, as well as G15S, P29S, and K116N mutations (that sit at or around the G-box domain in 3D), were all potent drivers for HNSCC tumorigenesis. This evidence concerns the gene RAC1 and head and neck squamous cell carcinoma.