Background: Squamous cell carcinoma (SCC) is the most common malignancy of the upper limb, and can pose a significant therapeutic challenge. Early treatment needs to be radical whilst maintaining function. Methods: We describe two cases of upper limb squamous cell carcinoma treated with radiotherapy, review the literature on radiotherapy as a primary treatment modality, and discuss the specific difficulties treating SCC in the hand. Results: Radiation therapy was inadequate in tumor clearance in both cases, with recurrence both extensive and distal to the initial focus. Moreover, both patients developed progressive functional loss related to pain, swelling, and stiffness. Conclusion: The evidence basis for radiation therapy as a primary modality is limited, although clearance rates are comparable to surgery. Both radiotherapy and surgery can be utilized to treat SCC. However, we make the case for the hand being especially susceptible to the unwanted side effects of radiotherapy.