Routes for HSC engineering. Directed differentiation of ES and iPS cells relies on morphogens and growth factors to recapitulate hematopoietic development in vitro. Direct conversion utilizes TFs to force somatic cells to switch cell fate without transitioning through normal developmental intermediates. TF combinations employed to convert heterologous cell types to hematopoietic cells are listed. Combinations in lowercase indicate conversions in mouse cells and those in uppercase represent conversions in human cells. Conversions from PSCs comprise a distinct approach. The pink arrows show direct conversions between cell types, the blue arrows show direct hematopoietic induction from PSCs using TF combinations, and the green arrows represent a hybrid strategy of directed differentiation and direct conversion, termed “respecification.” Extensive molecular analysis must be combined with functional interrogation to assess the relatedness of the engineered cell types to their native counterparts. ES/iPS, embryonic stem/induced PSCs; MPP, multipotent progenitor; MLP, multilymphoid progenitor; NK, natural killer; CMP, common myeloid progenitor; ES-HPC, embryonic stem-derived hematopoietic progenitor cells; YS-HPC, yolk sac-derived hematopoietic progenitor cells.