Cancer stem cells (CSCs) were first proposed 50 years ago, suggesting that tumors grow similarly to healthy tissues through a small number of dedicated stem cells. Recent studies have shown that many tumors contain CSCs in specialized niches, but identifying and eliminating them is not as straightforward as initially thought. New research using lineage tracing and cell ablation has revealed CSC plasticity, quiescence, renewal, and therapeutic response. This review discusses recent developments in the CSC field in light of new insights into normal stem cell biology. Expectations in the field have become more realistic, yet therapies based on the CSC concept are showing initial success. Tissues like the intestinal epithelium and hematopoietic system continuously self-renew through a population of tissue-specific stem cells. The CSC theory suggests that tumors are similarly fueled by a small number of tumor stem cells. This theory explains clinical observations such as tumor recurrence, dormancy, and metastasis. Over the past decade, many studies have identified CSCs in various cancers, including leukemia, breast cancer, colorectal cancer, and brain cancer. The CSC concept has inspired innovative treatment strategies targeting CSCs rather than just tumor bulk. The CSC concept was shaped by research on hematopoietic stem cells (HSCs), which are rare, quiescent, and self-renewing. HSCs generate all blood lineages and are multipotent. Their hierarchical organization has been used to interpret experimental observations of tissue renewal and cancer. Xenotransplantation assays have been used to assess CSC activity, showing that many cancers contain functionally heterogeneous populations of cancer cells. For example, human breast cancer cells can be engrafted into immune-deficient mice, with some cells capable of initiating tumors. The standard CSC model suggests that tumors are hierarchically organized, with rare self-renewing CSCs at the top. These CSCs are resistant to standard chemotherapy and radiation, which target non-CSCs. However, recent studies have shown that CSCs can be abundant and proliferate vigorously, and that stem cell hierarchies may be more plastic than previously thought. This plasticity complicates the identification and eradication of CSCs. Studies in mouse tumors have shown that CSCs can be identified through lineage tracing, revealing their hierarchical organization. For example, in intestinal adenomas, lineage tracing confirmed the presence of CSCs. In breast cancer, lineage tracing showed that some clones initially grow but eventually disappear, while others expand to become dominant. These findings support the presence of stem cells in primary intestinal adenomas. In human cancers, lineage tracing techniques have been used to study CSCs in organoids and xenografts. These studies have shown that LGR5+ colorectal cancer cells produce progeny over long periods, with slower kinetics than normal cells. These findings support the presence of hierarchies in human colorectal cancers. Recent studies have shown that adult stem cells can be abundant in nichCancer stem cells (CSCs) were first proposed 50 years ago, suggesting that tumors grow similarly to healthy tissues through a small number of dedicated stem cells. Recent studies have shown that many tumors contain CSCs in specialized niches, but identifying and eliminating them is not as straightforward as initially thought. New research using lineage tracing and cell ablation has revealed CSC plasticity, quiescence, renewal, and therapeutic response. This review discusses recent developments in the CSC field in light of new insights into normal stem cell biology. Expectations in the field have become more realistic, yet therapies based on the CSC concept are showing initial success. Tissues like the intestinal epithelium and hematopoietic system continuously self-renew through a population of tissue-specific stem cells. The CSC theory suggests that tumors are similarly fueled by a small number of tumor stem cells. This theory explains clinical observations such as tumor recurrence, dormancy, and metastasis. Over the past decade, many studies have identified CSCs in various cancers, including leukemia, breast cancer, colorectal cancer, and brain cancer. The CSC concept has inspired innovative treatment strategies targeting CSCs rather than just tumor bulk. The CSC concept was shaped by research on hematopoietic stem cells (HSCs), which are rare, quiescent, and self-renewing. HSCs generate all blood lineages and are multipotent. Their hierarchical organization has been used to interpret experimental observations of tissue renewal and cancer. Xenotransplantation assays have been used to assess CSC activity, showing that many cancers contain functionally heterogeneous populations of cancer cells. For example, human breast cancer cells can be engrafted into immune-deficient mice, with some cells capable of initiating tumors. The standard CSC model suggests that tumors are hierarchically organized, with rare self-renewing CSCs at the top. These CSCs are resistant to standard chemotherapy and radiation, which target non-CSCs. However, recent studies have shown that CSCs can be abundant and proliferate vigorously, and that stem cell hierarchies may be more plastic than previously thought. This plasticity complicates the identification and eradication of CSCs. Studies in mouse tumors have shown that CSCs can be identified through lineage tracing, revealing their hierarchical organization. For example, in intestinal adenomas, lineage tracing confirmed the presence of CSCs. In breast cancer, lineage tracing showed that some clones initially grow but eventually disappear, while others expand to become dominant. These findings support the presence of stem cells in primary intestinal adenomas. In human cancers, lineage tracing techniques have been used to study CSCs in organoids and xenografts. These studies have shown that LGR5+ colorectal cancer cells produce progeny over long periods, with slower kinetics than normal cells. These findings support the presence of hierarchies in human colorectal cancers. Recent studies have shown that adult stem cells can be abundant in nich