Genomic integrity is constantly challenged by DNA damaging agents such as reactive oxygen species (ROS). Consequently, DNA damage can compromise the fidelity and efficiency of essential DNA metabolic processes, including replication and transcription, which may contribute significantly to the etiology of many human diseases. Here, we review one family of DNA lesions, the epimeric 2-deoxyribose lesions, which arise from the improper chemical repair of the 2-deoxyribose radicals. Unlike most other DNA lesions, the epimeric 2-deoxyribose lesions are indistinguishable from their corresponding unmodified nucleosides in both molecular mass and chemical reactivity. We placed our emphasis of discussion on the formation of these lesions, their impact on the structure and stability of duplex DNA, their biological consequences, their potential therapeutic relevance, and future research directions about these modified nucleosides.