Cisplatin plus 5-fluorouracil (5-FU) (PF regimen) induction chemotherapy (IC) has been studied over the last two decades and has proven to be a durable and effective therapy for patients with locally advanced squamous cell cancer of the head and neck (SCCHN). Although randomized trials and meta-analyses have demonstrated that PF-based IC improves survival, reduces systemic metastases, and permits organ preservation, the effect on overall survival has been less robust than the results seen with cisplatin-based chemoradiotherapy (CRT) regimens. Differences in trial design, scheduling, and surgical interventions account for some of the variation in results. As studies have evolved, it has become evident that there are advantages to both approaches. This perception has led to the concept of sequential therapy (ST), the combination of IC, CRT, and surgery. ST programs are being studied intently in many centers. Phase II and III trials of ST regimens have reported unprecedented survival results in patients with locally advanced disease. In addition, the hypothesis that PF plus a taxane may result in an improved survival, compared to PF alone, for patients with locally advanced SCCHN on ST treatments is being tested in phase III trials. Although ST has not been compared head to head with CRT, early results support the use of this treatment paradigm in patients with poor prognosis SCCHN and should lead to definitive phase III trials in the near future. ST may represent the cutting edge of therapy for patients with curable, locally advanced SCCHN.