<p>Hematopoietic cells and lymphocytes arise from a common stem cell for both lineages. This explains why similar signaling networks regulate the development and biological functions of these cells. One crucial regulatory mechanism involves interactions with soluble mediators of innate immunity, including activated elements of the complement cascade (ComC). For many years, ComC proteins were thought to be synthesized only in the liver and released into blood to be activated by one of the three proteolytic cascades. The regulatory effects of activated components of ComC on hematopoietic stem progenitor cells (HSPCs) and mature hematopoietic cells have been well demonstrated in the past. However, recent data indicate that complement proteins are also expressed in several cell types, including lymphocytes and innate immune cells. This intracellular complement network has been named the “complosome.” Recent evidence from our group shows that the complosome is also expressed in HSPCs and plays an important yet underappreciated role in the expansion, trafficking, and metabolism of these cells. We propose that the complosome, like its role in lymphocytes, is necessary for the optimal function of mitochondria in hematopoietic cells, including HSPCs. This opens a new area for investigation and potential pharmacological intervention into the complosome network in normal and malignant hematopoiesis.</p><p></p>