In this perspective, we discuss how oncostatin M (OSM) and its receptor OSMR regulate tumor cells as well as mesenchymal and endothelial cells, which are key components of hematopoietic stem cell and tumor stem cell niches, and how these mechanisms could explain the poor prognosis associated with high expression of OSM and OSMR in hematological and non-hematological malignancies. Here, OSMR is linked to neoplasm.