Apoptosis or programmed cell death plays a pivotal role in regulating tissue homeostasis in the adult and in tissue remodeling during embryogenesis. As in other tissues, apoptosis plays an important role within the hematopoietic system in removing aged and non-functional cells. It plays a particularly important role in regulating the cells of the immune system. The signals and molecules regulating apoptosis in these immune cells have been intensely investigated over the years, providing great insight into the mechanisms involved. In contrast, much less is known about the regulation and role of apoptosis in the cells that produce differentiated hematopoietic cells, namely the hematopoietic stem cells (HSCs). It is appreciated that HSCs are under tight regulatory control, as either excessive proliferation or apoptosis will result in too many or too few hematopoietic cells (for example, leukemia or anemia). Apoptosis thus plays an essential role in maintaining the appropriate balance of HSC and mature blood cells and in protecting the HSC pool for life-long hematopoiesis. This review summarizes the current knowledge concerning apoptosis and its role in the physiology of the hematopoietic system, especially within the HSC compartment.