The authors report herein two diagnostically challenging cases centered on the myeloid/natural killer (myeloid/NK) cells, a variant of myeloblasts, to illustrate the importance of advanced flow cytometric immunophenotyping and an updated understanding of surface markers in hematopoietic malignancies. Myeloid/NK cell acute leukemia is a very rare subtype of leukemia. Although its NK-cell nature is debatable, it represents a variant of leukemia with distinct morphological and immunophenotypical features. The first case is a de novo myeloid/NK-cell acute leukemia with a striking clinical, morphologic and immunophenotypic resemblance to acute promyelocytic leukemia (APL), but which could be distinguished by its CD11a, CD18, CD117 and CD9 expression. This case illustrates the importance of utilizing the APL surrogate surface phenotype of HLA-DR(low), CD11a(low) and CD18(low) by flow cytometric study to rule in/out APL immunophenotypically. In the second case, we show that myeloid/NK-cell blasts can present as a variant of blasts in a preleukemic disease as refractory anemia with excess blasts-1 (RAEB-1), where the blasts were negative for CD34, CD117 and HLA-DR. The recognition of such blast variant is important in appropriately classifying such preleukemic diseases by blast percentage.