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Head and neck squamous cell carcinoma (HNSCC), the most prevalent pathological subtype of head and neck carcinoma (HNC), can be potentially cured if diagnosed at early stages and adequately treated. Still, most patients are diagnosed at stages III or IV disease, with estimated local and distant failure rates of 60% and 30%, respectively, notwithstanding aggressive multimodality curative intent treatment strategies approved. The excellent results of the EXTREME trial published in 2008 showing a median overall survival (mOS), of 10.1 months for patients with recurrent and/or metastatic (R/M) HNSCC, treated with platinum plus fluorouracil (5FU) and cetuximab, changed the standard of care (SOC), for these patients. The EXTREME regime was the first to evidence an overall survival (OS) benefit before the immunotherapy era, in this context. Two immunotherapy drugs are currently approved for treatment of R/M HNSCC in first or subsequent lines of treatment both for platinum-resistant and platinum sensitive disease: the anti-PD-1 agents nivolumab and pembrolizumab. But does this mean that there is no longer a place for the EXTREME regimen or for chemotherapy in general in R/M HNSCC treatment? And if there is, how to choose between available therapeutic options? In this article, the authors will address these questions by analyzing data from the main trials that investigated nivolumab and pembrolizumab in this setting.