The authors present a critical appraisal of the biological bases of altered fractionation and a brief overview of published randomized trials with conventional fractionation as the control arm, reviews and meta-analysis on altered fractionation radiotherapy in head and neck cancer. The major controversial issues emerging from these studies are reviewed and the limiting factors which so far have prevented the widespread use of altered fractionation regimens in current clinical practice are analyzed. Future perspectives regarding predictive biological assays for patient selection and the integration of altered fractionation regimens with radiochemotherapy protocols, biomodulators and novel radiotherapy techniques are also reviewed and summarized.