Hematopoietic stem cells (HSCs) are defined as primitive cells that are capable of both self-renewal and differentiation into any of the hematopoietic cell lineages. HSC numbers need to be precisely regulated to maintain hematopoietic homeostasis. HSCs undergo several cell fate decisions, including decisions on life and death and self-renewal and differentiation, which have crucial roles in the regulation of their numbers and lifespan. Defects in these processes have been found to contribute to hematopoietic insufficiencies and the development of hematopoietic malignancies. Recent studies have begun to elucidate how HSCs make life and death decisions and the underlying molecular mechanisms involved, highlighting the importance of a balance between survival and death in the regulation of HSCs.