The mainstay treatment of localized non-melanoma skin cancer (NMSC) is surgical excision or Mohs surgery. However, approximately 5% of patients with NMSC harbor high-risk clinicopathologic features for loco-regional recurrence, and distant metastasis. Prognostic factors such as close or positive margins, tumor size ≥ 2 cm, poor tumor differentiation, perineural invasion, depth of invasion, and immunosuppression have all been associated with increased loco-regional recurrence and impaired survival rates. In these patients more aggressive treatments are needed and radiotherapy (RT) is often discussed as adjuvant therapy after surgical resection. Due to the retrospective setting and the heterogeneity of the available studies, indications for adjuvant RT in patients with localized resected NMSC harboring high-risk features remain debated. Studies highlighting the limitations of our current understanding of the independent prognosis of each risk factor are needed to better define the role of adjuvant RT on outcome of localized NMSC and standardize its indications in the clinical setting.