Alternative splicing expands the transcriptome thereby promoting protein diversity. It governs critical cellular processes such as differentiation, proliferation and apoptosis in a tissue-specific manner. Aberrant splicing consequent to mutations in splicing factors and disruption of isoform ratios in key regulatory genes provides an important contribution to the pathogenesis of the myelodysplastic syndromes and myeloid leukemia. We review here the central role of alternative splicing in regulating myelopoiesis, and provide clear examples of how global splicing disruption or specific aberrant splicing events might promote leukemogenesis. We discuss the growing number of mechanistic links between epigenetic factors and alternative splicing. Finally, we address the potential utility of alternatively spliced isoforms as biomarkers and the development of novel therapies that modulate alternative splicing in myeloid and other malignancies.