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Leukemia remains a leading cause of hematologic cancer deaths despite advances in chemotherapy and immunotherapies such as Chimeric Antigen Receptor (CAR) T-cells, largely due to drug resistance, immune evasion, and relapse. This narrative review examines how CRISPR-based technologies are being applied to leukemia therapeutics through precise genome editing and functional genetic screens. It first synthesizes current literature on how CRISPR-Cas9 and next-generation editors (including Cas12a, Cas13, base editors, and prime editors) enable the engineering of universal allogeneic CAR-T cells and hematopoietic stem cells through disrupting immune checkpoints and Human Leukocyte Antigen (HLA) genes, correcting pathogenic mutations, and reducing graft-versus-host disease. The review then discusses pooled and arrayed CRISPR knockout, interference, and activation screens in which leukemia cells are subjected to selective forces, including chemotherapeutic agents and immune-mediated selective pressures, to enable the identification of genetic regulators of cell growth, survival, and antigen escape. Genome-wide dropout screens in acute myeloid leukemia have revealed leukemia-specific “fitness genes” in chromatin regulation, DNA repair, and metabolism whose pharmacologic inhibition recapitulates CRISPR-induced cytotoxicity. In addition, focused screens have identified subtype-specific dependencies, such as the vesicle-tethering factor Unconventional Secretion Organelle 1 (USO1) in B-cell acute lymphoblastic leukemia, as well as synthetic lethal gene pairs that provide a framework for rational combination therapies. Comparative analyses with RNA interference and computational essentiality frameworks further sharpen the distinction between core-essential and leukemia-selective targets. Collectively, the studies reviewed demonstrate how CRISPR-based screening and therapeutic strategies are reshaping target discovery pipelines and accelerating the development of more precise, effective, and less toxic treatment approaches across leukemia subtypes.