Most of cancers still remain to be incurable human diseases. According to recent findings, especially targeting cancer stem cells (CSCs) is the most issued therapeutic strategy. CSCs take charge of a cancer hierarchy, harboring stem cell-like properties involving self-renewal and aberrant differentiation potential. Most of all, presence of CSCs is closely associated with tumorigenesis and therapeutic resistance. Despite the numerous efforts to target CSCs, current anti-cancer therapies are still impeded by CSC-derived cancer malignancies; increased metastases, recurrence, and even acquired resistance after the anti-CSC therapies developed in experimental models. One of the most forceful underlying reasons is a “cancer heterogeneity” due to “CSC plasticity”. Comprehensive understanding of CSC-derived heterogeneity will provide novel insights for the establishment of efficient targeting strategies to eliminate CSCs. Here we introduce findings on mechanisms of CSC reprogramming and CSC plasticity, which give rise to phenotypically varied CSCs. Also we suggest concepts on improved CSC-targeted therapy to overcome therapeutic resistance caused by CSC plasticity and heterogeneity.