Abstract Myelodysplastic Syndromes (MDS) are heterogenous and poorly understood hematopoietic stem cell (HSC) failure syndromes common in individuals >60 years of age. With increased life expectancies, the incidence of MDS continues to rise, and will soon be the most prevalent hematologic disorder in elderly. There are no effective treatments for MDS patients, due to an insufficient understanding of the underlying pathobiology and a lack of faithful mouse models. Our research program is focused on filling these gaps, and then leveraging the resulting knowledge and tools to develop effective drug therapies. Already, we have discovered genetically-driven aberrant activation of innate immune pathways in MDS HSCs. We have also identified a critical function of innate immune pathways in normal HSCs, which has implications for chronic immune-related disorders, cardiovascular diseases, and hematopoiesis. We hypothesize that dysregulated innate immune signaling is a major contributor to the initiation and development of MDS, and is a feasible therapeutic target. Herein, we propose to test this hypothesis by carrying out the following complimentary 3-part research program: (1) Dissect the genetic and cellular underpinnings of MDS HSCs, with an emphasis on cell-intrinsic and cell-extrinsic immune-inflammatory factors. (2) Identify and characterize novel signaling pathways driving MDS phenotype in HSCs. (3) Develop novel therapeutic strategies for the treatment of MDS. The results of our research program will advance our paradigm-shifting model of the initiation, progression, and treatment of MDS.