High-risk non-melanoma skin cancer (NMSC) of the head and neck is difficult to manage, given its propensity for regional metastasis, perineural invasion, direct parotid invasion, and bony destruction. Management of these tumors demands awareness of the characteristics contributing to their recurrence. Recent studies emphasize the importance of treatment of the parotid gland and cervical lymph nodes to improve locoregional control. A multidisciplinary approach to the assessment and treatment of high-risk NMSC is required to provide comprehensive care. This review also covers recent advances in the understanding of NMSC biology and new approaches in chemoprevention.