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 supply of blood for transfusion. Production of mature blood cells from hematopoietic stem cells 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 biomanufacture of platelets. We describe the scale required for platelet biomanufacture to deliver sufficient cells for transfusion, provide a brief outline of the current understanding of megakaryopoiesis and thrombogenesis, and highlight how the current understanding impacts the design of culture systems and bioreactors for producing platelets.