Blocking the epidermal growth factor receptor (EGFR) represents a role model for a successful biological targeting approach to improving outcomes after radiotherapy. This review summarizes data from several local tumour control experiments in which EGFR inhibitors were combined with radiation in FaDu human squamous cell carcinomas xenografted into nude mice. BIBX1382BS is an oral bioavailable inhibitor of the intracellular tyrosine kinase domain of EGFR. It was administered in different experimental settings: concurrent with fractionated radiotherapy, following completion of irradiation, and in the period between surgery and adjuvant irradiation. Despite beneficial effects on tumour growth, in none of these experimental settings did BIBX1382BS improve local tumour control. In contrast, cetuximab (Erbitux), an IgG1 monoclonal antibody against the extracellular ligand-binding domain of EGFR, improved local tumour control when given concurrently with radiation. Results from a series of local tumour control experiments designed to elucidate the underlying mechanisms of cetuximab suggest that multiple radiobiological mechanisms might contribute to the observed effects: decreased number of clonogenic tumour cells, increased cellular radiation sensitivity, decreased repopulation and improved reoxygenation of clonogenic tumour cells during the combined treatment. In summary, the data suggest that different classes of EGFR inhibitors may have a different potential to improve local tumour control after fractionated irradiation.