Research investigations on various sources of stem cells have been conducted for potential to exert tissue regeneration, reverse immune-enhancement, and protect against tissue insult. At a more distant goal, it is likely that stem cells could be applied to medicine via organogenesis. However, the field of stem cells is not new since immune replacement via bone marrow transplantation is considered a successful form of cell therapy. There is evidence that stem cell therapies are close for several disorders such as neurodegeneration, immune hyperactivity, and functional insufficiencies such as Type I diabetes mellitus. The field of stem cell biology is gaining a strong foothold in science and medicine as the molecular mechanisms underlying stem cell behavior are gradually being unraveled. Although stem cells have tremendous therapeutic applicability in the aforementioned conditions, their uniqueness may also confer adverse properties, rendering them a double-edged sword. The discovery that stem cells have immortal and resilient characteristics has shed insight into the link between stem cells and tumorigenesis. Specifically, recent advancements in cancer research have implicated that a stem cell may be responsible for the refractoriness of cancers to conventional treatment such as chemotherapy and radiation. Here, we summarize the recent advancements in the cancer stem cell hypothesis and present the challenges associated with targeting resistant cancers in the context of stem cell microenvironments.