02250nas a2200229   4500000000100000008004100001260001500042100003800057700002100095700002900116700001900145700002500164700003000189700002600219700002800245245006700273856003800340300001100378490000700389520161000396022001402006       2024                            d  c2024-03-061 aMauricio Goncalves da Costa Sousa1 aSofia M. Vignolo1 aCristiane Miranda Franca1 aJared Mereness1 aMay Anny Alves Fraga1 aAlice Corrêa Silva-Sousa1 aDanielle S. W. Benoit1 aLuiz Eduardo Bertassoni00aEngineering models of head and neck and oral cancers on-a-chip  uhttps://doi.org/10.1063/5.0186722  a0215020 v183 aHead and neck cancers (HNCs) rank as the sixth most common cancer globally and result in over 450 000 deaths annually. Despite considerable advancements in diagnostics and treatment, the 5-year survival rate for most types of HNCs remains below 50%. Poor prognoses are often attributed to tumor heterogeneity, drug resistance, and immunosuppression. These characteristics are difficult to replicate using in vitro or in vivo models, culminating in few effective approaches for early detection and therapeutic drug development. Organs-on-a-chip offer a promising avenue for studying HNCs, serving as microphysiological models that closely recapitulate the complexities of biological tissues within highly controllable microfluidic platforms. Such systems have gained interest as advanced experimental tools to investigate human pathophysiology and assess therapeutic efficacy, providing a deeper understanding of cancer pathophysiology. This review outlines current challenges and opportunities in replicating HNCs within microphysiological systems, focusing on mimicking the soft, glandular, and hard tissues of the head and neck. We further delve into the major applications of organ-on-a-chip models for HNCs, including fundamental research, drug discovery, translational approaches, and personalized medicine. This review emphasizes the integration of organs-on-a-chip into the repertoire of biological model systems available to researchers. This integration enables the exploration of unique aspects of HNCs, thereby accelerating discoveries with the potential to improve outcomes for HNC patients.  a1932-1058