Adult stem cells, which are characterized by self-renewal and multi-potency, are classified as specialized cell types, responsible for the regeneration of damaged tissues. There is growing evidence that senescence of stem cells (or stem cell aging) is closely associated with a variety of aging-related diseases such as tissue atrophy, degenerative diseases and onset of cancers. Alterations in the systemic environment during aging may trigger stress signaling in stem cells and reduce stem cell characteristics, resulting in loss of differentiation potential and defective self-renewal (referred to as mal-differentiation). Thus, it has been suggested that aging-related disorders such as retarded regeneration of damaged tissue and onset of cancer may result from the mal-differentiation of stem cells. In particular, many types of cancers such as leukemia, intestinal cancer, skin cancer and sarcoma have been shown to originate from adult stem cells after a variety of oncogenic challenges. This review summarizes recent studies on cancers originating from stem cells, demonstrating possible molecular mechanisms that govern the susceptibility of stem cells to oncogenic challenges.