Head and neck squamous cell carcinomas (HNSCCs) are among the most aggressive and complex malignancies, with standard treatments including surgery, radiotherapy, chemotherapy, or their combinations. However, around 50% of patients do not benefit from these treatments, and severe toxic side effects are common. Decades of research have focused on understanding the genetics of HNSCC malignant cells, but the tumor microenvironment (TME) plays a crucial role in both progression and treatment response. Cancer-associated fibroblasts (CAFs), the primary source of extracellular matrix (ECM) and pro-tumoral components in the TME, are activated by cancer cells through secreted molecules, leading to phenotypic changes, increased secretion, and altered ECM production. CAFs modulate cell cycle, stemness, epithelial-mesenchymal transition (EMT), and resistance to targeted and chemoradiotherapy in HNSCC cells. This review highlights the importance of understanding the crosstalk between CAFs and tumor cells, and discusses the development of HNSCC tumor models to better understand this interaction and provide preclinical testing platforms for current and emerging therapeutics. Key advancements in single-cell and multiomics data analysis have revealed the crucial role of TME components, including CAFs, in HNSCC treatment failure. The review also addresses open questions, such as the lack of standardized methods to differentiate CAFs from normal fibroblasts and the need for more effective 3D in vitro models that closely mimic the TME to predict patient responses to treatment.Head and neck squamous cell carcinomas (HNSCCs) are among the most aggressive and complex malignancies, with standard treatments including surgery, radiotherapy, chemotherapy, or their combinations. However, around 50% of patients do not benefit from these treatments, and severe toxic side effects are common. Decades of research have focused on understanding the genetics of HNSCC malignant cells, but the tumor microenvironment (TME) plays a crucial role in both progression and treatment response. Cancer-associated fibroblasts (CAFs), the primary source of extracellular matrix (ECM) and pro-tumoral components in the TME, are activated by cancer cells through secreted molecules, leading to phenotypic changes, increased secretion, and altered ECM production. CAFs modulate cell cycle, stemness, epithelial-mesenchymal transition (EMT), and resistance to targeted and chemoradiotherapy in HNSCC cells. This review highlights the importance of understanding the crosstalk between CAFs and tumor cells, and discusses the development of HNSCC tumor models to better understand this interaction and provide preclinical testing platforms for current and emerging therapeutics. Key advancements in single-cell and multiomics data analysis have revealed the crucial role of TME components, including CAFs, in HNSCC treatment failure. The review also addresses open questions, such as the lack of standardized methods to differentiate CAFs from normal fibroblasts and the need for more effective 3D in vitro models that closely mimic the TME to predict patient responses to treatment.