In recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M-SCCHN), the armamentarium of systemic anti-cancer modalities continues to grow in parallel with innovations in and better integration of local approaches. The backbone of cytotoxic chemotherapy remains cisplatin with 5-fluorouracil or a taxane. In contrast to cisplatin, the tumoricidal activity of carboplatin monotherapy is debatable. Adding the epidermal growth factor receptor (EGFR) inhibitor cetuximab to a platinum/5-fluorouracil doublet (the so-called EXTREME regimen) produced a statistically but also clinically significant improvement of survival and became thus the standard first-line palliative treatment in adequately fit patients. Interestingly, three large randomized trials (EXTREME, SPECTRUM, and ZALUTE) evaluating different anti-EGFR monoclonal antibodies (cetuximab, panitumumab, and zalutumumab, respectively) demonstrated preferential anti-tumour efficacy in patients with primary cancer in the oral cavity. Modern immunotherapy with immunomodulating antibodies, dubbed immune checkpoint inhibitors, such as anti-programmed cell death protein-1 (anti-PD-1) inhibitors nivolumab and pembrolizumab, showed unprecedented activity in one first-line (KEYNOTE-048) and several second-line trials (CheckMate-141, KEYNOTE-012, KEYNOTE-055, and KEYNOTE-040). In a minority of also heavily-pretreated patients, these agents generate long-lasting responses without the typical chemotherapy-related toxicity, however, at a price of a low overall response rate, rare but potentially life-threatening immune-related adverse events, the risk of hyperprogression, and high costs. In oligometastatic disease, emerging data indicate long-term benefit with locally ablative techniques including metastasectomy and stereotactic radiotherapy of pulmonary but also hepatic and other distant lesions. In the frame of highly-individualized cancer care, a particularly intriguing approach is a combination of systemic and local therapies.