As transforming growth factor‐β (TGF‐β) and PTEN/PI3K/Akt pathways are among the most frequently altered signaling routes in the process of HNSCC development, Pten deletion in the mice head and neck epithelia gives rise to the activation of PI3K/Akt pathway, and loss of Tgfbr1 in the head and neck epithelia enhances paracrine effect of TGF‐β on the tumor stroma. Here, PTEN is linked to head and neck squamous cell carcinoma.