The leukocyte immunoglobulin (Ig)-like receptors (LILRs), is constituted by five inhibitory subpopulations (LILRB1-5) and six stimulatory subpopulations (LILRA1-6). The LILR populations substantially reside in immune cells, especially myeloid cells, functioning as a regulator in immunosuppressive and immunostimulatory responses, during which the nonclassical MHC class I molecules are widely involved. In addition, LILRs are also distributed in certain tumor cells, implicated in the malignancy progression. Collectively, the suppressive Ig-like LILRB2 is relatively well-studied to date. Herein, we summarized the whole family of LILRs and their biologic function in various diseases upon ligation to the critical ligands, therefore providing more information on their potential roles in these pathological processes and giving the clinical significance of strategies targeting LILRs.