The direct reprogramming of human somatic cells to induced pluripotent stem cells (iPSCs) offers exciting prospects for disease modelling and regenerative medicine. Several recent reports support the feasibility of generating various blood cell types from iPSCs through in vitro-directed differentiation. However, the derivation of hematopoietic stem cells (HSCs) capable of long-term reconstitution of all hematopoietic lineages appears to be more challenging. These hurdles notwithstanding, cell engineering strategies aiming to correct genetic defects at the stem cell level are already emerging. Robust methodologies for the generation of definitive human HSCs conferring high-level, multilineage, long-term, hematopoietic reconstitution thus are direly needed before the therapeutic potential and safety of iPSC-derived cell products can be thoroughly investigated.