Molecular diagnostics inhabit an increasingly central role in characterizing hematopoietic malignancies. This brief review summarizes the genomic targets important for many major categories of hematopoietic neoplasia by focusing on disease pathogenesis. In myeloid disease, recurrent mutations in key functional classes drive clonal hematopoiesis, on which additional variants can specify clinical presentation and accelerate progression. Lymphoblastic leukemias are frequently initiated by oncogenic fusions that block lymphoid maturation while, in concert with additional mutations, driving proliferation. The links between genetic aberrations and lymphoma patient outcomes have been clarified substantially through the clustering of genomic profiles. Finally, the addition of next-generation sequencing strategies to cytogenetics is refining risk stratification for plasma cell myeloma. In all categories, molecular diagnostics shed light on the unique mechanistic underpinnings of each individual malignancy, thereby empowering more rational, personalized care for these patients.