Erythrocytes and platelets are the major cellular components of blood. Several hereditary diseases affect the production/stability of red blood cells (RBCs) and platelets (Plts) resulting in anemia or bleeding, respectively. Patients with such disorders may require recurrent transfusions, which bear a risk to develop alloantibodies and ultimately may result in transfusion product refractoriness. Cell culture models enable to unravel disease mechanisms, and to screen for alternative therapeutic products. Besides these applications, the ultimate goal is the large-scale production of blood effector cells for transfusion. Cultured RBCs that lack many of the common blood group antigens and Plts-lacking HLA expression would improve transfusion practice. Large numbers of RBCs and Plts can already be generated using hematopoietic stem cells derived from fetal liver, cord blood, peripheral blood, and bone marrow as starting material for cell culture. The recent advances to generate blood cells from induced pluripotent stem cells provide a donor-independent, immortal primary source for cell culture models. This enables us to study developmental switches during erythropoiesis/megakaryopoiesis and provides potential future therapeutic applications. In this review, we will discuss how erythropoiesis and megakaryopoiesis are mimicked in culture systems and how these models relate to the in vivo process.