Research in the last few years has revealed a sophisticated interaction network between multiple bone marrow (BM) cells that regulate different hematopoietic stem cell (HSC) properties, such as proliferation, differentiation, localization and self-renewal during homeostasis. These mechanisms are essential to keep the physiological HSC numbers in check and interfere with malignant progression. Besides the identification of multiple mutations and chromosomal aberrations driving the progression of myeloid malignancies, alterations in the niche compartment recently gained attention in contributing to disease progression. Leukaemic cells can remodel the niche into a permissive environment favoring leukaemic stem cell (LSC) expansion over normal HSC maintenance, and evidence is accumulating that certain niche alterations can even induce leukaemic transformation. Relapse after chemotherapy is still a major challenge during treatment of myeloid malignancies and cure is only rarely achieved. Recent progress in the understanding of niche-imposed chemoresistance mechanisms will likely contribute to the improvement of current therapeutic strategies. This Perspective article discusses the role of different niche cells and their stage- and disease-specific roles during progression of myeloid malignancies and in response to chemotherapy.