The Cancer Stem Cell (CSC) concept, proposed five decades ago, suggests that tumor growth is driven by a small number of dedicated stem cells, similar to the renewal of healthy tissues. Recent studies have provided insights into the plasticity, quiescence, renewal, and therapeutic response of CSCs. This review discusses new developments in the CSC field, including the changing understanding of normal stem cell biology and the challenges in identifying and eradicating CSCs. It highlights the plasticity of CSCs and non-CSCs, the role of the microenvironment in CSC plasticity, and the metabolic adaptations of CSCs. The review also explores the therapeutic targeting of CSCs, including the use of epigenetic regulators, antibody-drug conjugates, and niche targeting strategies. Despite the progress, the complex nature of CSCs and their niches presents significant challenges for effective therapy. The review concludes by emphasizing the need for further research to better understand the dynamics of CSCs and their niches to develop more effective treatments.The Cancer Stem Cell (CSC) concept, proposed five decades ago, suggests that tumor growth is driven by a small number of dedicated stem cells, similar to the renewal of healthy tissues. Recent studies have provided insights into the plasticity, quiescence, renewal, and therapeutic response of CSCs. This review discusses new developments in the CSC field, including the changing understanding of normal stem cell biology and the challenges in identifying and eradicating CSCs. It highlights the plasticity of CSCs and non-CSCs, the role of the microenvironment in CSC plasticity, and the metabolic adaptations of CSCs. The review also explores the therapeutic targeting of CSCs, including the use of epigenetic regulators, antibody-drug conjugates, and niche targeting strategies. Despite the progress, the complex nature of CSCs and their niches presents significant challenges for effective therapy. The review concludes by emphasizing the need for further research to better understand the dynamics of CSCs and their niches to develop more effective treatments.