During hematopoiesis, members of the Bcl-2 family are essential regulators of homeostasis determining the survival and differentiation of progenitors. Aberrations in their expression promote pathological conditions including immune deficiency, autoimmunity, and cancer. Over the past two years, several new roles for Bcl-2 family members have been identified during hematopoietic differentiation. Anti-apoptotic Mcl-1 has been identified to be the essential pro-survival molecule during early hematopoiesis. Later in myeloid development Mcl-1 exhibits a selective role being required for the terminal stages of granulocyte development but is dispensable for monocytic differentiation. During red blood cell development, the pro-apoptotic BH3-only family member Nix has recently been defined as the essential negative regulator of terminal erythrocyte differentiation. This review will address the apoptotic pathways that regulate these critical control points during hematopoiesis.