Since the advent of the genomic era, remarkable advances have been made in molecular diagnostic capabilities for patients with rare genetic diseases. Within the field of nonmalignant hematology, these advances have had a particularly dramatic impact on the diagnosis and treatment of patients with genetic disorders causing decreased production and survival of hematopoietic stem and progenitor cells, known collectively as the inherited bone marrow failure syndromes (IBMFS). Most IBMFS are also leukemia predisposition syndromes, placing patients at high risk for developing clonal hematopoiesis, which can later progress to myelodysplastic syndrome (MDS) and eventually to myeloid leukemia. The wide availability of polymerase chain reaction (PCR)-based rapid sequencing methodologies, high-throughput next-generation sequencing panels, and whole exome sequencing has enabled the identification of many novel IBMFS and MDS/leukemia predisposition syndromes. Refinement in genomic diagnostics has also allowed detection of novel variants in known IBMFS genes to the extent that recommendations now clearly indicate that all patients with pediatric MDS not associated with prior chemotherapy or acquired aplastic anemia should have germline testing for IBMFS-associated gene mutations, given the high likelihood of identifying variants. Furthermore, these advances in genomic medicine over the past two decades have facilitated new algorithmic approaches to patient management that integrate genetic diagnoses with phenotypic features. In this new era, patients can access treatment methodologies tailored to their specific condition, optimizing outcomes for these rare and complex disorders.