Killer cell lectin-like receptor G1 (KLRG1) is an immune checkpoint receptor primarily expressed on NK and T-cell subsets, playing a crucial role in downregulating immune cell activation and proliferation. Accumulating evidence highlights KLRG1 as a significant biomarker and therapeutic target in various diseases, including autoimmune disorders, infectious diseases, and cancers. Blocking KLRG1 has shown promising results in reducing the effects of downregulation in mouse tumor models. However, the understanding of KLRG1 expression and its mechanisms in different diseases remains incomplete. This review explores the distribution, structure, and signaling pathways of KLRG1 in immune cells, summarizing its expression patterns and roles in disease development and progression. Additionally, it discusses the potential applications of KLRG1 as a tool for tumor immunotherapy, emphasizing the synergistic efficacy of KLRG1 inhibitors combined with other targeted inhibitors. The review also highlights the differences between KLRG1 in mice and humans, the regulatory pathways of KLRG1, and its impact on immune cells, diseases, and therapeutic strategies.Killer cell lectin-like receptor G1 (KLRG1) is an immune checkpoint receptor primarily expressed on NK and T-cell subsets, playing a crucial role in downregulating immune cell activation and proliferation. Accumulating evidence highlights KLRG1 as a significant biomarker and therapeutic target in various diseases, including autoimmune disorders, infectious diseases, and cancers. Blocking KLRG1 has shown promising results in reducing the effects of downregulation in mouse tumor models. However, the understanding of KLRG1 expression and its mechanisms in different diseases remains incomplete. This review explores the distribution, structure, and signaling pathways of KLRG1 in immune cells, summarizing its expression patterns and roles in disease development and progression. Additionally, it discusses the potential applications of KLRG1 as a tool for tumor immunotherapy, emphasizing the synergistic efficacy of KLRG1 inhibitors combined with other targeted inhibitors. The review also highlights the differences between KLRG1 in mice and humans, the regulatory pathways of KLRG1, and its impact on immune cells, diseases, and therapeutic strategies.