Reprogramming somatic cells to pluripotency, especially by the induced pluripotent stem cell (iPSC) technology, has become widely used today to generate various types of stem cells for research and for regenerative medicine. However the mechanism(s) of reprogramming still need detailed elucidation, including the roles played by the leukemia inhibitory factor (LIF) signaling pathway. LIF is central in maintaining the ground state pluripotency of mouse embryonic stem cells (ESCs) and iPSCs by activating the Janus kinase-signal transducer and activator of transcription 3 (JAK-STAT3) pathway. Characterizing and understanding this pathway holds the key to generate naïve pluripotent human iPSCs which will facilitate the development of patient-specific stem cell therapy. Here we review the historical and recent developments on how LIF signaling pathway regulates ESC pluripotency maintenance and somatic cell reprogramming, with a focus on JAK-STAT3.