<p>Leukemia, characterized by a heterogeneous spectrum of malignancies arising from the clonal expansion of hematopoietic progenitor cells, continues to represent a significant challenge within the field of oncology. Notwithstanding advancements in diagnostic techniques, therapeutic strategies, and prognostic tools, the complexities surrounding the pathogenesis of leukemia and its diverse clinical manifestations highlight the imperative need for the identification of novel biomarkers aimed at improving patient outcomes. The C-type lectin-like molecule-1 (CLL-1) has recently gained recognition as a particularly promising and appealing therapeutic target within the realm of leukemia. This cell surface receptor is characterized by an exceptionally high expression level on acute myeloid leukemia (AML) blasts. The consistent presence of CLL-1 on these cells not only emphasizes its prospective utility as a therapeutic target but also positions it as an optimal candidate for the surveillance of minimal residual disease (MRD). Furthermore, CLL-1 showcases innovative potential for the formulation of new immunotherapeutic strategies designed to combat leukemia. This narrative review aims to explore the structure, function, and diverse expression patterns of CLL-1 in relation to leukemia, thereby offering critical insights into its pivotal role in the disease’s pathogenesis and its potential ramifications for treatment. The investigation of CLL-1 as a feasible target for diagnostic purposes, MRD monitoring, and the creation of novel immunotherapy strategies heralds the commencement of new and promising pathways for therapeutic approaches employed in the management of leukemia. A comprehensive understanding of the complex interplay between CLL-1 and the pathogenesis of leukemia will undeniably contribute to the design and advancement of more targeted and efficacious therapeutic interventions.</p>