Leukocyte immunoglobulin (Ig)-like receptors [LILRs, also known as Ig-like transcripts (ILTs)] are a family of inhibitory and stimulatory receptors encoded within the leukocyte receptor complex and are expressed by immune cell types of both myeloid and lymphoid lineage. Several members of the LILR family recognize major histocompatibility complex class I. The immunomodulatory role of LILR receptors indicates that they may exert an influence on signaling pathways of both innate and adaptive immune systems. LILR activity can also influence the antigen-presenting properties of macrophages and dendritic cells and may thus play a role in T-cell tolerance. The wide-ranging effects of LILR signaling on immune cell activity imply that these receptors are likely to play an important role in a range of clinical situations including pregnancy, transplantation, and arthritis (including the human leukocyte antigen B27-associated spondyloarthropathies). In this review, we summarize current knowledge on the nature and function of LILRs, focusing on their regulation of immune cell activity and their potential role in disease.