Killer-cell immunoglobulin-like receptor 2DL4 (KIR2DL4), a member of the killer cell immunoglobulin-like receptors (KIRs) family, plays an important role in the regulation of the immune system, which is expressed primarily on natural killer (NK) cells. Human leucocyte antigen-G (HLA-G), a non-classical major histocompatibility complex (MHC) class I molecule, is the only known ligand of KIR2DL4. Accumulating evidence has shown that KIR2DL4 has emerged as a potential target for enhancing the antitumor immune response. Elevated expression of KIR2DL4 has been observed in certain tumor types, including melanoma, lung cancer, and ovarian cancer, indicating its role in tumor evasion. Our previous study had shown that blockade of KIR2DL4 interaction in NK cells can re-sensitize breast cancer to trastuzumab treatment, which indicated that KIR2DL4 was a pivotal immune checkpoint of NK cells. Currently, there are several therapeutic approaches targeting KIR in cancer immunotherapy. However, there are no efficient cancer immunotherapy strategy targeting KIR2DL4. In this review, we aim to summarize and discuss the potential role of KIR2DL4 as a target for cancer immunotherapy. A better understanding of KIR2DL4 might be helpful to develop effective KIR2DL4-targeted therapies, which could provide new treatment options for cancer patients.