Abstract: In recent years, the clinical implementation of next-generation sequencing (NGS) has demonstrated the critical driving role of specific myeloid-related gene mutations in the clonal evolution of myelodysplastic syndrome (MDS). These molecular genetic abnormalities not only correlate significantly with disease prognosis but also provide actionable molecular targets for precision medicine-era therapies. In current clinical practice, the Revised International Prognostic Scoring System (IPSS-R) remains the primary tool for guiding risk-adapted treatments in patients with MDS. However, real-world outcomes in certain patients still deviate from IPSS-R predictions, highlighting the need to integrate molecular genetic features into traditional prognostic models for enhanced accuracy. This article systematically reviews recent advances in understanding MDS genetic mutations, focusing on their pivotal roles in driving malignant clonal evolution, optimizing risk stratification, and developing personalized treatments.