Introduction: Myeloid malignancies are caused by uncontrolled proliferation of neoplastic cells and lack of mature hematopoietic cells. Beside intrinsic genetic and epigenetic alterations within the neoplastic population, abnormal function of the bone marrow stroma promotes the neoplastic process. To overcome the supportive action of the microenvironment, recent research focuses on the development of targeted therapies, inhibiting the interaction of malignant cells and niche cells.Areas covered: This review covers regulatory networks and potential druggable pathways within the hematopoietic stem cell niche. Recent insights into the cell-to-cell interactions in the bone marrow microenvironment are presented. We performed literature searches using PubMed Database from 2000 to the present.Expert opinion: Future therapy of myeloid malignancies must focus on targeted, personalized treatment addressing specific alterations within the malignant and the supporting niche cells. This includes treatments to overcome resistance mechanisms against chemotherapeutic agents mediated by supporting microenvironment. Novel techniques employing sequencing approaches, Crisp/Cas9, or transgenic mouse models are required to elucidate specific interactions between components of the bone marrow niche to identify new therapeutic targets.