This article gives an overview on different current strategies of assay-based response evaluation in head and neck squamous cell carcinomas (HNSCC) and critically summarizes their role and needs for future clinical evaluation. Due to a growing amount of data of phase III clinical trials of multimodality treatment options for HNSCC, treatment planning in regard to optimal outcome is becoming an interdisciplinary challenge. New concepts such as induction chemotherapy with bi- or ternary combinations of chemotherapeutics, integration of targeted therapies, concurrent and sequential chemoradiation concepts, and multimodality-based organ preservation strategies strongly compete with traditional definitive surgical procedures. Moreover, the outcome is difficult to predict due to heterogeneity of a tumor's response, impaired late functional outcome, and increased late toxicity if simultaneously applied to radiation. Retrospectively looking at non-responders with tumors classified as resectable, primary surgery is very likely to have achieved better results, since chemoradiation causes a high degree of early and late toxicities leading to extremely complicated terms and conditions in surgery following current multimodal therapeutic strategies. Unfortunately, predictive information on response characteristics of a given tumor before starting the therapy is not available in daily routine, although heterogeneity in response of a given tumor entity to treatments has been known for decades. Therefore, current therapy strategies for HNSCC still have to ignore this fact, creating an urgent need for the development of proper predictive assays. There are interesting clinical observations showing that response on induction chemotherapy may predict the outcome after radiotherapy. Some trials use this empiric phenomenon to pre-select non-responders for primary surgical treatment avoiding severe salvage complications after failure of complete chemoradiation treatment. Moving one step further, recent literature and our own investigations implicate that response evaluation of the individual patient's HNSCC in a suitable ex vivo assay just before starting the treatment is mature for clinical research. To this end, essential needs and hints are addressed and discussed.