Human Leukemia Inhibitory Factor (LIF) is a multifunctional cytokine belonging to the IL-6 family—which includes IL-6, IL-11, oncostatin M (OSM), ciliary neurotrophic factor (CNTF), cardiotrophin-1 (CT-1), cardiotrophin-like cytokine factor 1 (CLCF1), and IL-27—all of which signal through receptor complexes containing the shared gp130 subunit. LIF binds to the LIF receptor (LIFR) in association with gp130, activating JAK/STAT3, MAPK, and PI3K signaling pathways that regulate cell survival, differentiation, immune modulation, and tissue repair. In humans, LIF plays critical roles in embryonic implantation and endometrial receptivity, hematopoiesis, neural development, and maintenance of stem cell pluripotency. LIF-mediated STAT3 signaling is also involved in modulation of inflammatory responses and tissue regeneration; however, dysregulated LIF expression has been implicated in fibrosis, chronic inflammatory diseases, and tumor progression in cancers such as breast, pancreatic, and colorectal cancer, where it can promote tumor cell survival and stromal remodeling. Because of its dual roles in regeneration and pathology, human LIF is an important therapeutic target and biomarker in reproductive medicine, oncology, and fibrotic disease research. Characterization of LIF signaling continues to inform development of STAT3-modulating therapies and strategies aimed at balancing tissue repair with control of chronic inflammation and malignancy.