Abstract Leukemias are heterogeneous diseases characterized by aberrant hematopoietic stem and progenitor cells (HSPCs). Oncogenic fusion genes and proteins, produced via gross chromosomal rearrangements, such as chromosomal translocation, insertion, and inversion, play important roles in hematologic malignancies. These oncoproteins alter fundamental cellular properties, such as self-renewal, differentiation, and proliferation, and confer leukemogenic potential to HSPCs. In addition to providing fundamental insights into the process of leukemic transformation, these fusion genes provide targets for treatment and monitoring of myeloid leukemias. Furthermore, new technologies such as next-generation sequencing have allowed additional insights into the nature of leukemic fusion genes. In this review, we discuss the history, biologic effect, and clinical impact of fusion genes in the field of myeloid leukemias.