Of all the haemopoietic processes occurring in the bone marrow, the production of megakaryocytes (MKs) and, subsequently, platelets is perhaps the most complex and unusual. Beginning with the haemopoietic stem cell, a sequence of proliferation and differentiation steps produces MK progenitors, megakaryoblasts and eventually MKs. Unique among blood precursors, the MK undergoes a process of endomitosis, producing a polyploid cell with a multiple of the normal chromosome complement (up to 64N). Following this, the focus of the maturation process moves to the cytoplasm. Complex invagination of the plasma membrane causes the cytoplasm to become intricately subdivided by a system of demarcation membranes. These provide a source of membrane material which, together with granules and organelles, is transported into ‘proplatelets’, pseudopodia elongating from the MK and producing numerous plateletsized swellings, which bud off to be released as functional platelets. A complex reorganisation of the cytoskeleton allows the sequence of proplatelet formation, platelet budding and detachment to be completed successfully. Predictably, the senescent MK nucleus left after platelet release is disposed of by apoptosis and phagocytosis. It has become evident, however, that a specialised form of apoptosis is engaged during the process of proplatelet formation and the release of mature platelets. In cultured MKs derived from CD34+ bone marrow cells, activation of caspase-3 and-9, mitochondrial membrane permeabilisation and cytochrome c release were all evident in maturing MKs, suggesting a process of apoptosis. Proplatelet formation could be diminished either by exposure of cells to caspase inhibitors or by overexpression of Bcl-2 (De Botton et al., 2002). Intriguingly, caspase activation prior to proplatelet maturation showed a localised distribution, rather than the diffuse pattern encountered later in the senescent MK. Further evidence of the highly compartmentalised nature of these apoptotic events comes from observations of an exclusion from the proplatelet pseudopodia and budding platelets of both mitochondrial permeability transition and caspase-9 (Clarke et al., 2003), allowing released platelets to remain viable despite emerging from a dying MK. Thus, platelets differ from the nonfunctional, thrombogenic and short-lived apoptotic bodies produced during a conventional apoptosis. What are the signals controlling these events? MK survival, proliferation and differentiation are coordinated and controlled by combinations of cytokines and mediators presented within specialised bone marrow ‘niches’. Interaction with a vascular niche appears to be required for the final stages of MK maturation and platelet release (Avecilla et al., 2004). Thrombopoietin (TPO) is the essential growth factor for adequate platelet production, but stem cell factor, IL-3, IL-6 and IL-11 all play important roles at different developmental stages. Mouse knockouts for either TPO or its ligand c-mpl show a profound thrombocytopenia; nevertheless, there remains a residual thrombopoiesis that produces MKs and platelets which are morphologically and functionally normal (Bunting et al., 1997). The principal role of TPO therefore appears to be the maintenance of MK numbers, but the final differentiation of MKs to proplatelets and mature platelets depends upon other signalling systems. Chemokines such as stromal-derived factor 1 and fibroblast growth factor 4 help localise MKs to the vascular niche within the bone marrow (Avecilla et al., 2004) and glutamate signalling via the N-methyl-D-aspartate (NMDA) receptor is implicated in the terminal differentiation of MKs …