The purpose of this article is to review the most significant results of the clinical studies conducted in the past two decades by the EORTC Head and Neck Cancer Group (HNCG). As for phase III trials, the HNCG investigated, besides the efficacy of chemopreventive drugs, the impact of cytostatic agents on various therapeutic targets, in combination or not with surgery and chemotherapy. These targets were: (a) chemo-prevention in curatively treated early stage disease; (b) organ preservation programmes in patients with operable tumour, comparing immediate surgery versus first-line chemotherapy; (c) postoperative management of locally advanced tumours, comparing radio-chemotherapy versus radiotherapy alone. Other phase II and phase III studies were also completed to investigate drug activity in advanced and/or recurrent head and neck squamous cell and adenoid cystic carcinomas. The present article will also analyse the strategies developed within the Group in the field of translational research.