Head and neck squamous cell carcinomas (HNSCCs) are aggressive and heterogeneous cancers with limited treatment success. The tumor microenvironment (TME), particularly cancer-associated fibroblasts (CAFs), plays a critical role in tumor progression and treatment resistance. CAFs, the main stromal component of HNSCC, are activated by tumor-secreted molecules, leading to phenotypic changes and altered ECM production. They modulate cell cycle, stemness, epithelial-mesenchymal transition (EMT), and resistance to therapy through interactions with secreted molecules or direct contact with the ECM. Co-culture and 3D models of tumor cells and TME components allow for studying HNSCC tumor milieu and modulating hypoxia and reprogramming cancer stem cells (CSCs). This review discusses the development of HNSCC tumor models with CAFs to better understand their interactions with tumor cells and provide preclinical testing platforms for current and emerging therapies. CAFs are highly heterogeneous, with no specific markers to identify subtypes. They are derived from activated fibroblasts, bone marrow fibrocytes, mesenchymal stem cells, and stellate cells. CAFs can account for 80% of the tumor mass in late-stage HNSCC and are associated with poor survival outcomes. They play a key role in tumor progression and treatment resistance by inducing cancer cell stemness, activating EMT, promoting proliferation, invasion, and immune modulation. 3D co-culture models are promising for studying TME interactions and developing more effective therapies. Key signaling pathways mediating CAF-tumor cell crosstalk include TGF-β, MAPK, EGFR, Hippo, Jak/STAT, Wnt, and Notch pathways. TGF-β promotes cancer cell stemness, EMT, and therapy resistance, while MAPK and EGFR pathways are involved in cell proliferation, survival, and invasion. The Hippo pathway regulates cell proliferation, stemness, and invasion, and the Jak/STAT pathway is involved in cell proliferation, stemness, and therapy resistance. The Wnt pathway is involved in cell stemness, chemoresistance, and tumor growth, while the Notch pathway is involved in tumor progression and angiogenesis. HPV-positive HNSCCs have distinct pathophysiological mechanisms and clinical characteristics compared to HPV-negative HNSCCs. HPV-positive HNSCCs have fewer genetic mutations and are more radiosensitive, leading to better responses to radiotherapy. CAFs support immune evasion and proinflammatory activities by increasing the expression of proinflammatory genes and growth factors. CAFs are involved in both earlier stages of HPV-related carcinogenesis and prolonged stimulation for maintenance of cancer cells, including acquisition of stemness and EMT phenotype. Current research investigates the differential expression and function of CAFs in HPV+ and HPV− HNSCC and demonstrates significantHead and neck squamous cell carcinomas (HNSCCs) are aggressive and heterogeneous cancers with limited treatment success. The tumor microenvironment (TME), particularly cancer-associated fibroblasts (CAFs), plays a critical role in tumor progression and treatment resistance. CAFs, the main stromal component of HNSCC, are activated by tumor-secreted molecules, leading to phenotypic changes and altered ECM production. They modulate cell cycle, stemness, epithelial-mesenchymal transition (EMT), and resistance to therapy through interactions with secreted molecules or direct contact with the ECM. Co-culture and 3D models of tumor cells and TME components allow for studying HNSCC tumor milieu and modulating hypoxia and reprogramming cancer stem cells (CSCs). This review discusses the development of HNSCC tumor models with CAFs to better understand their interactions with tumor cells and provide preclinical testing platforms for current and emerging therapies. CAFs are highly heterogeneous, with no specific markers to identify subtypes. They are derived from activated fibroblasts, bone marrow fibrocytes, mesenchymal stem cells, and stellate cells. CAFs can account for 80% of the tumor mass in late-stage HNSCC and are associated with poor survival outcomes. They play a key role in tumor progression and treatment resistance by inducing cancer cell stemness, activating EMT, promoting proliferation, invasion, and immune modulation. 3D co-culture models are promising for studying TME interactions and developing more effective therapies. Key signaling pathways mediating CAF-tumor cell crosstalk include TGF-β, MAPK, EGFR, Hippo, Jak/STAT, Wnt, and Notch pathways. TGF-β promotes cancer cell stemness, EMT, and therapy resistance, while MAPK and EGFR pathways are involved in cell proliferation, survival, and invasion. The Hippo pathway regulates cell proliferation, stemness, and invasion, and the Jak/STAT pathway is involved in cell proliferation, stemness, and therapy resistance. The Wnt pathway is involved in cell stemness, chemoresistance, and tumor growth, while the Notch pathway is involved in tumor progression and angiogenesis. HPV-positive HNSCCs have distinct pathophysiological mechanisms and clinical characteristics compared to HPV-negative HNSCCs. HPV-positive HNSCCs have fewer genetic mutations and are more radiosensitive, leading to better responses to radiotherapy. CAFs support immune evasion and proinflammatory activities by increasing the expression of proinflammatory genes and growth factors. CAFs are involved in both earlier stages of HPV-related carcinogenesis and prolonged stimulation for maintenance of cancer cells, including acquisition of stemness and EMT phenotype. Current research investigates the differential expression and function of CAFs in HPV+ and HPV− HNSCC and demonstrates significant