Leukocyte immunoglobulin-like receptors, subfamily B (LILRBs), are a class of critical immunosuppressive receptors that contribute to immune homeostasis by transmitting suppressive signals upon binding to ligands such as major histocompatibility complex class I molecules. They play key roles in modulating both innate and adaptive immune responses. This review summarizes the structural features, ligand interactions, signaling pathways, and expression regulation of LILRBs, and discusses their roles in immune cell function and disease progression, particularly in the tumor microenvironment. We also review current progress in the development of LILRB-targeted therapies for hematological malignancies and solid tumors and outline the challenges and future directions in translating these findings into clinical applications. By integrating recent advances, this review provides a framework for understanding the potential of LILRBs as therapeutic targets in cancer and immune-related disorders.