This paper reviews the molecular mechanisms involved in HNC, summarizing the signaling pathways harboring genetic aberrations (RAS–RAF–MEK–ERK, PIK3–AKT–mTOR, WNT/beta-catenin, JAK-STAT, NOTCH, and HIF–VEGF), epigenetic mechanisms and the roles of ncRNAs and tumor microenvironment in neoplastic progression. Here, AKT1 is linked to neoplasm.