Treatment options for patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) have evolved over the past decade and have helped improve survival outcomes for patients. Most national and regional guidelines recommend first-line therapy with an immune checkpoint inhibitor (with or without chemotherapy) or a cetuximab-based regimen, by assessment of expression levels of the biomarker programmed cell death-ligand 1 (PD-L1). However, patient- and tumor-specific factors, including the patient's age, comorbidities, performance status, and tumor burden, kinetics and spread also need to be considered to optimize treatment in the first line. Additionally, with increasing availability of newer therapies globally, it is crucial to customize the subsequent second- or later-line therapy based on patient characteristics, including the previous therapy received. This review highlights the factors that should be considered for treatment decision-making in patients with R/M SCCHN. It also summarizes the current evidence for clinical outcomes based on treatment sequencing and provides guidance on choosing an optimal treatment regimen for patients in the first-line treatment setting and beyond.