We hypothesised that dysregulation of the ligand-induced internalisation of EGFR, known as receptor-mediated endocytosis, impacts on the efficacy of the MAb treatments directed at this receptor. We additionally hypothesised that dysregulation of EGFR localisation would impact on the pathobiology and pathogenesis of SCC. A technique was developed to analyse EGFR trafficking status in live tissue from human squamous cell carcinoma. We have now analysed this pre-teatment status and correlated our findings with patient outcome after anti-EGFR monoclonal antibody therapy. We find that trafficking status impacts patient outcome. We have further developed assays for tumour cell killing in response to anti-EGFR therapy and found that manipulation of cellular trafficking increases therapy efficacy. Additionally we present data on the mechanism of this increase. Findings from this work may also impact on the clinical management of other tumours in which target receptors are spatially regulated, including FGFR in melanoma, VEGF in colorectal carcinoma and IGFR in sarcomas.