Radiation-induced cutaneous vascular neoplasms occur infrequently and comprise benign, so-called atypical vascular lesions (AVL) and angiosarcomas (AS), often being high-grade malignant tumors. Both arise most frequently within previously irradiated skin in breast-conserving–treated mammary cancer patients. Because of the different clinical course and, consequently, different therapeutic approaches, histopathologic distinction of AVL and AS is essential but significant morphologic overlap has been documented. Furthermore, the coexistence of these lesions or progression of AVL into AS has rarely been reported. Whether AVL is a precursor of AS is much debated and unresolved to date. Recent interest has focused on genetic changes and their differences in AS and AVL. MYC amplification and expression of the corresponding protein has been identified in AS in comparison with AVL. Therefore, MYC fluorescent in situ hybridization and anti-MYC immunohistochemical analysis are diagnostically useful in difficult cases. Furthermore, advanced tailored treatment strategies in AS, one of the most aggressive type of sarcoma, rely on identifying genes and proteins involved in malignant angiogenesis.