© 2014 by John Wiley & Sons, Inc. All rights reserved. Leptin is an adipocyte-derived hormone involved in a myriad of physiological process, including the control of energy balance, glucose homeostasis, reproduction, growth, and the immune response. The leptin receptor (Ob-R) belongs to a member of the class I cytokine receptor super-family. Ob-R binding to leptin induces conformational changes that recruit JAKs (Janus kinases), which in turn phosphorylates Ob-R and activates STATs. Here, we briefly reviewed the role of leptin signaling in the regulation of stem cell and cancer stem cells (CSC), highlighting the leptin-mediated signaling pathways and its potential as a drug target. In addition, we introduced recently identified molecular mechanisms of leptin in CSC, tumor angiogenesis, as well as its cross talk with other signaling pathways. Novel opportunities could emerge from the discovery of leptin cross talk with inflammatory, angiogenic cytokines, and other oncogenic factors and their links to obesity-related cancers and CSC.