<p>Mesenchymal stromal cells (MSCs) have demonstrated therapeutic potential in hematologic diseases by modulating immune responses, supporting hematopoiesis, and remodeling the bone marrow microenvironment. Clinically, MSCs have been explored for graft-versus-host disease and hematopoietic stem cell transplantation support, while their applications in hematologic malignancies, including acute myeloid leukemia, multiple myeloma, and myelodysplastic syndromes, remain under investigation. However, therapeutic heterogeneity, safety concerns, and standardization challenges limit their clinical translation. Recent advances in MSC-derived extracellular vesicles, gene modification technologies, and integrative combination strategies have expanded the therapeutic landscape, enabling more precise and targeted modulation of immune responses and tumor microenvironments. Moreover, disease-specific evidence highlights the dual roles of MSCs—acting either as therapeutic agents or as contributors to disease progression—depending on stromal plasticity and niche conditioning. This review provides a comprehensive and mechanistic synthesis of MSC functions across both malignant and non-malignant hematologic disorders, integrating preclinical and clinical findings in immunoregulation, hematopoietic recovery, anti-fibrosis, and microenvironmental reprogramming. In addition, we critically evaluate emerging strategies to overcome translational bottlenecks, including inter-donor variability, lack of predictive potency markers, and the need for scalable, standardized manufacturing protocols. By bridging foundational mechanisms with translational potential, this review offers forward-looking perspectives to guide future optimization and clinical integration of MSC-based therapies in hematology.</p> Graphical Abstract <p></p>