Recent advent in next generation sequencing (NGS) and bioinformatics has generated an unprecedented amount of genetic information in myeloidmalignancies. This information may shed lights to the pathogenesis, diagnosis and prognostication of these diseases and provide potential targets for therapeutic intervention. However, the rapid emergence of genetic information will quickly outpace their functional validation by conventional laboratory platforms. Foundational knowledge about zebrafish hematopoiesis accumulated over the past two decades and novel genomeediting technologies and research strategies in thismodel organismhavemade it a unique and timely research tool for the study of human blood diseases. Recent studies modeling human myeloid malignancies in zebrafish have also highlighted the technical feasibility and clinical relevance of thesemodels. Careful validation of experimental protocols and standardization among laboratorieswill further enhance the application of zebrafish in the scientific communities and provide important insights to the personalized treatment ofmyeloid malignancies.