Leukemia inhibitory factor (LIF), a secreted cytokine, plays an important role in a wide array of biological processes including inducing differentiation of leukemia cell, inflammatory response, neuronal development, embryonic implantation, stem cell self-renewal and cancer progression, etc. LIF exerts its biological functions mainly through the activation and regulation of JAK/STAT3, AKT, EKR1/2 and mTOR signal pathways. The expression levels of LIF are regulated by many different factors under different conditions in different tissue/cell types. For example, estrogen and p53 are important regulators for the high LIF production in uterine tissues at the implantation stage. Hypoxia plays a critical role in LIF overexpression in solid tumors. Many cytokines, including IL-6, IL-1β, can also induce the LIF expression and production. In this review, we summarize the current understanding on the transcriptional regulation of LIF under various conditions.