Several challenges must be overcome before hematopoietic cells derived from pluripotent stem cells (PSCs) can be tested in the clinics. Pre-existing genetic mutations in somatic cells are a major concern for the production of iPSCs (induced pluripotent stem cells). This raises the question of what is the best somatic cell source to reprogram into iPSCs. Adult stem cells such as germ cell precursors and hematopoietic stem cells (HSCs) which are believed to be protected from somatic mutation accumulation are good candidates. Three gene editing methods have now been developed for human cells. Careful comparison of these methods is needed to determine the most appropriate for clinical applications. Differentiation of PSCs generally recapitulates early development. Therefore, cells produced from PSCs have an embryonic phenotype. Because transplantable HSCs and red blood cells expressing adult hemoglobin arise late in development, long after gastrulation, they have been difficult to produce from PSCs. The most difficult challenge is perhaps the development of methods to produce cells with an adult phenotype. Interestingly, recent reports suggest that primitive hematopoietic cells might make important contributions to adult hematopoiesis. Production of primitive hematopoietic cells might therefore have clinical applications.