Single nucleotide polymorphism arrays (SNP-A) have recently been widely applied as a powerful karyotyping tool in numerous translational cancer studies. SNP-A complements traditional metaphase cytogenetics with the unique ability to delineate a previously hidden chromosomal defect, copy neutral loss of heterozygosity (CN-LOH). Emerging data demonstrate that selected hematologic malignancies exhibit abundant CN-LOH, often in the setting of a normal metaphase karyotype and no previously identified clonal marker. In this review, we explore emerging biologic and clinical features of CN-LOH relevant to hematologic malignancies. In myeloid malignancies, CN-LOH has been associated with the duplication of oncogenic mutations with concomitant loss of the normal allele. Examples include JAK2, MPL, c-KIT, and FLT3. More recent investigations have focused on evaluation of candidate genes contained in common CN-LOH and deletion regions and have led to the discovery of tumor suppressor genes, including c-CBL and family members, as well as TET2. Investigations into the underlying mechanisms generating CN-LOH have great promise for elucidating general cancer mechanisms. We anticipate that further detailed characterization of CN-LOH lesions will probably facilitate our discovery of a more complete set of pathogenic molecular lesions, disease and prognosis markers, and better understanding of the initiation and progression of hematologic malignancies.