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Acute myeloid leukemia (AML) remains a formidable blood cancer, despite recent advances in treatment. A significant challenge persists in improving patient outcomes, particularly in addressing relapse and treatment resistance. Identifying new therapeutic targets is critical for advancing AML therapy. C-type lectin-like molecule-1 (CLL-1) has emerged as a promising therapeutic target in AML. This cell surface receptor is highly expressed on AML blasts and demonstrates stable expression throughout disease progression. CLL-1's consistent presence makes it an ideal candidate for monitoring minimal residual disease (MRD), which is a critical indicator for predicting relapse. Beyond its utility as a diagnostic marker, CLL-1 offers exciting potential in the development of immunotherapies. Emerging strategies, such as CAR-T-cell therapy and antibody-drug conjugates (ADCs), are being investigated to leverage the immune system against CLL-1-expressing AML cells. This review examines the structure, function, and expression patterns of CLL-1 in AML and other hematologic malignancies, providing insights into its role in disease pathogenesis and treatment potential. Exploring CLL-1 as a target for diagnosis, MRD monitoring, and immunotherapy opens new avenues for AML treatment. A deeper understanding of its relationship with AML pathogenesis will aid in the development of targeted therapies, offering hope for improved patient outcomes in the future.