RNA-binding proteins (RBPs) regulate fundamental processes, such as differentiation and self-renewal, by enabling the dynamic control of protein abundance or isoforms or through the regulation of noncoding RNA. RBPs are increasingly appreciated as being essential for normal hematopoiesis, and they are understood to play fundamental roles in hematological malignancies by acting as oncogenes or tumor suppressors. Alternative splicing has been shown to play roles in the development of specific hematopoietic lineages, and sequence-specific mutations in RBPs lead to dysregulated splicing in myeloid and lymphoid leukemias. RBPs that regulate translation contribute to the development and function of hematological lineages, act as nodes for the action of multiple signaling pathways, and contribute to hematological malignancies. These insights broaden our mechanistic understanding of the molecular regulation of hematopoiesis and offer opportunities to develop disease biomarkers and new therapeutic modalities.