ABSTRACT Human endogenous retroviruses (HERVs), remnants of ancient retroviral infections, comprise nearly 8% of the human genome and play dual roles in physiological regulation and disease pathogenesis. Once considered genomic “fossils,” HERVs are now known to dynamically influence gene expression, immunity, and homeostasis via epigenetic regulation, molecular mimicry, and viral mimicry. Their structural components, including long terminal repeats and conserved viral genes, enable them to act as regulatory elements and potential sources of novel antigens. However, the causal mechanisms linking the dysregulation of HERVs to diseases—the technical challenges in their detection and quantification, as well as their therapeutic potential—remain poorly systematized. This review synthesizes the molecular architecture and evolutionary trajectories of HERVs, emphasizing their tissue‐specific expression patterns. We further delineates their pathogenic roles in diseases including cancer, autoimmune conditions, and neurodegenerative disorders. Finally, we discuss emerging strategies targeting HERVs, including epigenetic modulators, immunotherapies, and gene editing, alongside ongoing clinical trials and translational challenges. By integrating molecular insights with clinical perspectives, this work provides a foundational framework for leveraging HERVs as biomarkers and therapeutic targets in precision medicine.