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Traditionally, megakaryopoiesis is the differentiation process that results in platelet production from hematopoietic stem cells (HSCs). Compared to other hematopoietic cell differentiations, this process is quite original in several aspects: (1) megakaryopoiesis can derive directly from the HSC, especially in cases of stress; (2) megakaryopoiesis and erythropoiesis are two close cell lineages with a common progenitor; (3) megakaryocytes are mostly giant cells whose polyploidization is an integral part of the differentiation process and not dependent on a stress; (4) platelets originate from the fragmentation of the megakaryocyte cytoplasm with a production that depends both on the number and the size of megakaryocytes; and (5) the process of fragmentation is active and depends on extrusion of long cytoplasmic extensions, called proplatelets, into the vascular sinusoids of the bone marrow where they will break under the blood flow forces into preplatelets and then into platelets. The last few years have seen major advances in the understanding of these different aspects of megakaryopoiesis, as well as about the role of thrombopoietin and its receptor (called MPL) in the regulation of platelet production. This knowledge has enabled a better understanding of many pathologies, in particular the mechanism of hereditary or acquired thrombocytopenia and thrombocytosis, and has led to new therapies such as the clinical development of thrombopoietin receptor agonists. Recently, however, completely unexpected data have been obtained, questioning the function of megakaryocytes. Although their main function is platelet production, megakaryocytes are heterogeneous: some of them are involved in the formation of the hematopoietic niche and regulate the HSC quiescence; others are involved in immune response, with functions close to those of monocytes or dendritic cells. Furthermore, the marrow is not the only site of megakaryopoiesis: the lung is a second site, developing an entire megakaryocyte differentiation, which may primarily lead to immune megakaryocytes. In addition, megakaryocytes essentially of marrow origin located in the lung circulation are also present and involved in platelet production. These data open up new perspectives on the role of megakaryocytes in the regulation of hematopoiesis and in innate immunity, particularly during pulmonary infection.