Since the discovery that hematopoiesis could be established by a single cell over five decades ago, advances in model systems, sequencing, reprogramming and genome editing technologies have enabled precise molecular characterization of regulators of hematopoiesis. These discoveries have informed and accelerated implementation of clinical trials for a broad of array of benign and malignant hematologic disorders, including bone marrow failure syndromes and leukemia, as well as guided the development of molecular prognostication strategies. This Keystone Symposia meeting will bring together basic, translational and clinical researchers to discuss key regulators of hematopoietic stem and progenitor cell ontogeny, cell fate specification and self-renewal during homeostasis, stress and malignant transformation. The relative importance of cell-autonomous genetic, epigenetic, transcriptional and post-transcriptional hematopoietic regulatory mechanisms as well as local niche or systemic factors will be presented by international leaders in the field of hematopoiesis and stem cell biology. The culmination of innovative genome editing, reprogramming, single-cell sequencing and imaging in different model systems to unravel essential regulators of hematopoiesis will be highlighted. This meeting should provide a vital opportunity for forging collaborations between researchers from disparate disciplines and result in novel insights from a plethora of model systems that will enable investigators to address basic, translational and clinical hematopoiesis research challenges.