Non-small cell lung cancer (NSCLC) is now regarded as the most common cause of cancer-related mortality in China. Despite continuous efforts to improve the therapeutic response, the overall five-year survival rate for NSCLC is still less than 15%. Now we have known that the growth of neoplastic tumors is maintained exclusively by a small subpopulation called "cancer stem cells" which posseses ability of self-renew and differentiation. It has been widely accepted that cancer stem cells are chemoresistant and radioresistant. Therefore, a major challenge in treating this and other cancers is the intrinsic resistance to conventional therapies demonstrated by the stem/progenitor cell that is responsible for the sustained growth, survival, and invasion of the tumor. Identifying these stem cells in non-small cell lung cancer and defining the biologic processes necessary for their existence are paramount in developing new clinical approaches with the goal of preventing disease recurrence. This review summarizes our update understandings of the cellular and molecular mechanisms operating within the putative cancer-initiating cells at the core of non-small cell lung cancer.