NK-large granular lymphocyte leukemia (NK-LGLL) is a lymphoid malignancy driven by constitutive activation of cellular pathways and chronic inflammation, underscoring the central role of the microenvironment in the disease's pathogenesis. Patients with NK-LGLL typically present with an expansion of mature NK cells displaying large granular lymphocyte morphology, a restricted killer Immunoglobulin-like receptor pattern and genetic lesions, including , , and mutations. NK-LGLL generally follows an indolent clinical course and rarely progresses to a stage requiring treatment. The rarity of the disease has significantly hampered precise diagnosis, a deeper understanding of its pathogenesis, the assessment of appropriate clinical trials, and even its classification. This review aims to present the latest insights into genetic, biological, and clinical features of this disorder. In particular, recent advances in genetics and epigenetics, along with emerging knowledge into the role of microenvironment, have uncovered new vulnerabilities in leukemic cells. These findings may have a meaningful impact on defining genomic-driven disease subsets and hold promise for improving outcomes in large granular lymphocyte leukemia patients through the development of personalized, innovative therapies.