"More than 30’000 patients with hematological malignancies greatly benefit from hematopoietic stem cell (HSC) transplants each year in Europe alone. However, availability of transplant material for afflicted patients, prognosis, and relapse-free survival are all hindered by the limited quantity of HSCs available for therapy. Despite several decades of research, HSC cannot be cultured in vitro without rapidly differentiating. This is largely due to our poor understanding of the mechanisms that regulate HSC fate in response to cues from their microenvironmental ‘niche’, and the difficulty to unveil these mechanisms using existing experimental model systems. Building on our extensive expertise in the engineering of artificial stem cell niches and microfluidic technology, here I propose to develop a novel in vitro bone marrow model to recapitulate its organ-level function in regulating HSC fate. A modular microfluidic system, termed ‘bone marrow-on-chip’, will be designed comprising a niche compartment, mimicking key anatomical, cellular and molecular characteristics of the HSC niche. This niche compartment will be coupled to a fluidic network, as a simplistic surrogate of the native circulation such as to inject and remove HSC progeny for various analyses. This should allow, for the first time, the in vitro modelling of dynamic physiological HSC processes such as the ‘homing’ of stem cells to the niche after transplantation, and the ‘mobilization’ of stem cells from the niche upon systemic stimulation. With this tool we will be able to gain insight into the cell types and factors found in HSC niches and how they influence HSC behavior in mice and humans, providing paths forward to designing novel HSC expansion procedures. The successful realization of this concept would represent a scientific and technological paradigm shift with impact beyond the field of hematopoiesis, opening up new horizons for the for the study of other stem cell and even tumor cell types."