Patients with locally advanced, operable head and neck squamous cell carcinoma (HNSCC) are known to be at high risk of treatment failure, ranging from local regrowth to lymphatic spread to systemic dissemination. Attacking specifically each of these patterns of failure implies the use of a multimodal approach. Throughout the past two decades the management of stages III/IV HNSCC remained a matter of debate, especially with regards to treatment intensity and sequencing. Surgery and/or radiotherapy were the mainstay of local-regional treatment in patients with locally advanced disease, but treatment outcome often remained disappointing. In the hope of improving the prognosis after radical surgery, cisplatin-based combinations have been administered before surgery, in the interval between surgery and radiotherapy, or after radiotherapy. Until very recently these combinations, at best, decreased systemic failures without having a real impact on local outcome or survival. Indeed, until the mid-1990s, most trials that had tested postoperative combinations of chemotherapy and radiotherapy did not show any significant benefit. In 2004 level I evidence was established with the publication of the results of two large-scale, independent but similar trials conducted in Europe and the U.S. Both studies demonstrated that, compared with postoperative irradiation alone, adjuvant concurrent chemoradiation was more efficacious in terms of local-regional control and disease-free survival. With the publication of these two trials the evidence demonstrating the potential value of concurrent postoperative chemoradiotherapy in high-risk operable head and neck cancer is strong; however, additional studies and comparative analysis of the selection criteria and treatment outcomes across these two trials will be needed to gain a more accurate assessment of benefit and risk levels in specific patients with operable, locally advanced disease.