Head and neck squamous cell carcinoma (HNSCC) comprises a heterogeneous group of tumors that arise from the squamous epithelium of the oral cavity, oropharynx, larynx and hypopharynx. While many HNSCCs are related to classical etiologic factors of smoking and alcohol, a clinically, genomically, and immunologically distinct subgroup of tumors arise from the epithelium of the tonsil and the base of tongue as a result of infection with Human Papilloma Virus (HPV). In this review we describe the genomic and immunologic landscape of HNSCC, highlighting differences between HPV-positive and HPV-negative HNSCC. While HPV-negative tumors are characterized by tobacco-associated mutations in genes including TP53 and CDKN2A, in HPV-positive HNSCC integration of viral genome from HPV into the host cellular genome results in expression of the E6 and E7 viral oncoproteins, with consequent degradation of p53 and functional inactivation of Rb. The immune microenvironment of HNSCC is characterized by changes in immune cell populations, immune checkpoints, as well as tumor or microenvironmental factors that alter the balance of the immune milieu in favor of immunosuppression, allowing tumor evasion and escape from immune surveillance. Immune therapies, in particular those targeting the PD1 receptor or its ligand PD-L1, including nivolumab, pembrolizumab, durvalumab, and atezolizumab have shown significant efficacy in subsets of patients with HNSCC. Current trials are evaluating the efficacy of these agents in combination with chemotherapy, radiotherapy and other immune therapies including CTLA-4 and IDO-1 inhibitors. While biomarkers including PD-L1 expression, PD-L2 expression and the interferon-gamma gene signature show potential to predict benefit from checkpoint inhibitor therapy - it is hoped that improved understanding of the genomic and immune landscape will lead to ways to improved strategies to stratify patients and to select which HNSCC are most likely to benefit from these therapies.