Hematopoietic stem cells (HSCs) are extremely useful in treating a wide range of diseases and have a variety of useful research applications. However, the routinely generated low in vitro concentrations of HSCs from current bioreactor manufacturing systems has been a hindrance to the full-scale application of these essential cellular materials. This has made the search for novel bioreactor systems for high-concentration HSC production a major research endeavour. This review addresses process challenges in relation to bioreactor development and optimisation for high-density HSC production under effective monitoring of essential culture parameters, such as pH, dissolved oxygen and nutrient uptake. It discusses different process strategies and bioreactor configurations for HSCs production from a commercial viability perspective, and also discusses recent advances in the field.