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Seventy to 90 percent of patients who have received radiation treatment struggle with radiation skin and mucosal toxicity. The inflicted damage to progenitor cells and local microcirculation makes it more likely that wounds, infections, and fibrosis may occur; lesions of variable severity often co-exist. Acute erythema, hyperpigmentation, and mild desquamation usually wane in weeks and require only minor treatment. Conversely, the management of persistent radiation dermatitis and telangiectasia remains unsatisfactory; chronic lesions may progress to tissue atrophy and disfiguring fibrosis. Protrophic, natural-origin polynucleotides, formulated as Class III medical devices, have long shown to be a reliable topical option to stop the progression of radiation-related lesions. The present review illustrates the rationale of polynucleotides in skin and mucosal radiodermatitis management. It also illustrates the clinical results in a series of exploratory clinical studies carried out with polynucleotide devices over the last decade. The examined studies open the way to the high-level clinical research program, which will develop over the next years.