Recent advances in functional genomics have paved the path toward improvement in disease modeling for hematologic malignancies such as acute myeloid leukemia (AML). Among these functional genomic approaches include genome-wide CRISPR screens, induced pluripotent stem (iPS) cell technology, viral- or vector-based approaches, and informatics-based approaches. As a prime example, induction of pluripotency in somatic cells has remarkable potential for understanding of disease systems and gaining insight into therapeutics. In the recent years, the molecular applications of this iPS technology have extended to multiple arenas within hematologic malignancies. In AML, the generation of iPS cells has informed our understanding of clonal evolution at the stem cell level. Human AML-iPS cells have been shown to procure leukemic phenotypes and functions and can chart clonal evolution of the entire disease. Furthermore, sequential CRISPR-based editing of human iPS cells can model clonal dynamics and can identify novel therapeutic targets. Our group has recently modeled clonal dynamics in TP53-mutant AML by annotating copy number variation against variant allele frequency to infer the subclonal structure. This focused review highlights functional genomic approaches in AML - namely how dynamic expression of genetic content within specific contexts in hematopoietic cells contributes to biological behavior and phenotypes of disease. We explore the use of these novel technologies towards molecular target validation for AML as of 2022.