Although the prognostic role of human papillomavirus (HPV) in locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN) is well established, its prognostic and/or predictive role in recurrent/metastatic settings remains to be defined. Despite epidemic growth of HPV-positive oropharyngeal carcinoma, a low recurrence rate in HPV-positive patients results in a small number of patients entering clinical trials for recurrent and/or metastatic SCCHN. The consequent lack of statistical power and also significant data contamination by misclassification of HPV-positive patients leads to premature study conclusions. Even emerging data from the analysis of 2 randomized trials, SPECTRUM and EXTREME, do not provide enough evidence for any HPV-based therapeutic strategy. Many upcoming studies for locally advanced disease, including the ones with de-escalated strategies, will have an increasing number of patients with HPV. Optimal HPV testing strategies for reliable patient selection and HPV-driven therapeutic approaches will be essential. Here, we comprehensively review the existing data regarding HPV status and prognostic or predictive outcomes in recurrent/metastatic settings and discuss current promising studies and future directions that may help in the design of upcoming trials.