<p>This review aimed to provide a comprehensive overview of the molecular landscape of HNSCC, focusing on key genetic alterations, epigenetic regulation, and therapeutic challenges associated with HNSCC. We highlighted the deregulations in key cellular signaling pathways, including PI3K/AKT/mTOR, Ras/Raf/MEK/ERK, Wnt/Beta-catenin, Notch, Hedgehog, Hippo-YAP/TAZ, and JAK/STAT, which contribute to tumor initiation, progression, and therapy resistance. In addition, we provided an overview of epigenetic mechanisms in HNSCC including DNA methylation changes, histone modifications, and non-coding RNA regulation. Emerging epigenetic therapeutic strategies under clinical investigation were also highlighted. Moreover, molecular and epigenetic signatures related to HPV-positive and HPV-negative HNSCC further emphasized the complexity and clinical heterogeneity of disease. Head and Neck Squamous Cell Carcinoma (HNSCC) represents a biologically complex malignancy characterized by molecular heterogeneity, high recurrence rate, and poor clinical outcome. A deeper understanding of the genetic and epigenetic mechanisms underlying HNSCC is essential for improving early diagnosis, and therapy response providing a better patient stratification. An extensive review of current literature was conducted using PubMed and Google Scholar which included 280 articles highlighting recent advancements in gene expression profiling in HNSCC. This review summarizes the complex molecular events in HNSCC emphasizing the key deregulations in cellular signaling pathways, differential gene expression regulated by epigenetic modifications. Understanding these molecular mechanisms may facilitate the identification of novel biomarkers and therapeutic targets, contributing to the development of more effective treatment for HNSCC.</p> Graphical abstract <p></p>