Cell outer membranes contain glycosphingolipids and protein receptors, which are integrated into glycoprotein microdomains, known as lipid rafts, which float freely in the membrane bilayer. These structures have an important role in assembling signaling molecules (eg, Rac-1, RhoH and Lyn) together with surface receptors, such as the CXCR4 receptor for α-chemokine stromal-derived factor-1, the α4β1-integrin receptor (VLA-4) for vascular cell adhesion molecule-1 and the c-kit receptor for stem cell factor, which together regulate several aspects of hematopoietic stem/progenitor cell (HSPC) biology. Here, we discuss the role of lipid raft integrity in the retention and quiescence of normal HSPCs in bone marrow niches as well as in regulating HSPC mobilization and homing. We will also discuss the pathological consequences of the defect in lipid raft integrity seen in paroxysmal nocturnal hemoglobinuria and the emerging evidence for the involvement of lipid rafts in hematological malignancies.