Management of metastatic head and neck squamous cell carcinoma is evolving as new systemic therapies have led to improvements in survival, and as advances in locoregional therapy and the increased numbers of patients with HPV-associated cancers who develop oligometastases raise the possibility of ablation of limited numbers of metastases. We review the data regarding first-line immunotherapy in PD-L1-expressing metastatic head and neck squamous cell carcinoma, the experience with aggressive local management of oligometastases, and promising novel immunotherapies, targeted therapies, and HPV-specific treatments. For patients with metastatic head and neck squamous cell carcinoma that is PD-L1 expressing, first-line systemic therapy is pembrolizumab or pembrolizumab with chemotherapy. Inclusion of chemotherapy is associated with higher objective response proportion in all biomarker subgroups and may have a greater impact on survival in HPV-associated cancers. For patients with oligometastatic disease, particularly when metastases are metachronous, current evidence supporting the role of local ablation is limited to a small number of retrospective studies. Based on retrospective data, patients with a smaller number of metastases, lung metastases, and/or virally associated head and neck squamous cell carcinoma are most likely to benefit from an aggressive ablative approach. Additionally, we review emerging evidence for targeted therapy in metastatic head and neck squamous cell carcinoma, including with agents that inhibit mutant HRAS or NOTCH1, or overexpressed EGFR. Studies of antiangiogenic agents in combination with immune checkpoint blockade, and combination immunotherapy, are also under study.