Combining treatment modalities has proven beneficial in advanced stages of head and neck cancer. While the majority of patients with an early disease stage can be cured by surgery or radiotherapy alone, these two approaches have to be brought together and even accompanied by chemotherapy to provide cure to about half of patients with locally and locoregionally advanced disease. Such multimodality treatments are the result of intensive clinical research spanning over several decades. In the most advanced cases presenting with distant metastases, a similar development is ongoing, i.e., from a single modality to multimodality approach. In this setting, the current standard-of-care option is systemic treatment only, comprising cytotoxic drugs associated with the epidermal growth factor receptor inhibitor cetuximab or with the programmed cell death-1 (PD-1) inhibitor pembrolizumab or pembrolizumab alone. The choice between different systemic agents depends on appraisal of several factors including the expression of the PD-1 ligand. However, the benefit of adding local to systemic treatment, albeit commonly utilized in clinical practice, has not been evaluated in randomized clinical trials so far. Contrastingly, systemic treatment repeatedly proved to significantly improve survival and quality of life in head and neck cancer. In patients with metastatic disease, local treatment can be delivered both to the distant and local or locoregional sites, aiming at better survival and/or quality of life and using different modalities not limited to surgery and radiotherapy but involving also radiofrequency ablation, cryotherapy, and others. The key decision factor is patient selection in the context of different clinical scenarios. If the objective is to eradicate distant metastases, available data show that patients with slowly progressing metastases that we have dubbed argometastases have the highest odds for survival, and even local therapy alone may be sufficient to attain this goal. In those considered for local therapy at the primary site despite distant dissemination, one of the main predictors for enhanced efficacy seems to be the intensity of local therapy which needs to meet criteria for a radical treatment. In this respect, a less intensive local approach in combination with systemic therapy does not improve survival. Finally, advances in the field of immunotherapy represent one of the highlights of the past decade, and current evidence indicates that a combination of local therapy with immunotherapy can be particularly beneficial. Moreover, it should not be overlooked that compared to new drug development, integration of local therapy to complement systemic treatment is a relatively affordable and accessible approach in both developed and developing countries.