Class I phosphoinositide 3-kinases which produce the D3-phosphoinositide second messenger phosphatidylinositol 3,4,5-trisphosphate in response to membrane receptors activation play a critical role in cell proliferation, survival, metabolism, and motility. These lipid kinases and the phosphatases regulating the level of D3-phosphoinositides have been an intense area of research these last two decades. The class I phosphoinositide 3-kinases signaling is found aberrantly activated in numerous human cancers, including in malignant hemopathies, and are important therapeutic targets for cancer therapy. Haematopoiesis is an ongoing process which generates the distinct blood cell types from a common hematopoietic stem cell through the action of a variety of cytokines. In the human adult hematopoiesis occurs primarily in the bone marrow, and defects in hematopoiesis result in diseases, such as anemia, thrombocytopenia, myeloproliferative syndromes, or leukemia. Here we give a brief overview of the role of class I phosphoinositide 3-kinases in hematopoietic stem cells, in hematopoietic lineage development and in leukemia, particularly in acute myeloid leukemia and summarize the potential therapeutic implications.