Platelets for transfusion, obtained from volunteer blood donors are a limited resource. Given the increased range of donor restrictions to prevent transmission of disease and the decline in volunteer blood donors there is a diminishing pool of blood for transfusion. Production of mature blood cells from hematopoietic stem cells (HSCs) via large-scale manufacture is an alternative way of meeting transfusion demands. In this review we provide a detailed outline of the challenges and opportunities for the bio-manufacture of platelets. We describe the scale required for platelet bio-manufacture to deliver sufficient cells for transfusion, a brief outline of the current understanding of megakaryopoiesis and thrombogenesis and highlight how this impacts on the design of culture systems and bioreactors for producing platelets.