ABSTRACT Although hematopoietic stem cell (HSC) therapy for hematological diseases can lead to a good outcome from the clinical point of view, the limited number of ideal donors, the comorbidity of patients and the increasing number of elderly patients may limit the application of this therapy. HSCs can be generated from induced pluripotent stem cells (iPSCs), which requires the understanding of the bone marrow and liver niches components and function in vivo. iPSCs have been extensively applied in several studies involving disease models, drug screening and cellular replacement therapies. However, the somatic reprogramming by transcription factors is a low-efficiency process. Moreover, the reprogramming process is also regulated by microRNAs (miRNAs), which modulate the expression of the transcription factors OCT-4 (also known as POU5F1), SOX-2, KLF-4 and MYC, leading somatic cells to a pluripotent state. In this Review, we present an overview of the challenges of cell reprogramming protocols with regard to HSC generation from iPSCs, and highlight the potential role of miRNAs in cell reprogramming and in the differentiation of induced pluripotent stem cells.