<p>Cancer metastasis contributes to the high mortality rate in patients and remains a significant challenge in treating solid malignancies. The limitations of current therapeutic interventions are underscored by the mere 5% survivorship of patients with metastatic disease. Since cancer stem cells (CSCs) are the major cause of metastatic spread, emerging therapeutic modalities specifically targeting CSCs present a lucrative approach to curtail metastatic disease. The literature demonstrating the promise of targeting CSCs to limit metastatic spread holds immense potential but remains scattered. This review provides concise knowledge of CSC targeting strategies and their impact on the metastatic burden in cancer patients. Current therapeutic strategies, early screening of cancer and reduction in smoking have drastically reduced the cancer-associated deaths by 34% in the US [<CitationRef CitationID="CR1">1</CitationRef>]. However, CSCs and therapy resistance pose major clinical challenges. Therefore, new way to address CSCs such as targeting stemness pathways, cellular plasticity and stress tolerance, nano theranostic approaches, the effect of phytochemicals and new radiotherapy technologies such as microbeam radiotherapy are being extensively studied. The detailed molecular studies on CSCs provide a platform for identifying factors intrinsic to cancer cells, host cells, and tumor microenvironment (TME) influencing stemness and overall metastasis. In addition to emerging anti-metastasis therapeutic modalities, the review provides information regarding exclusive targets and signalling molecules involved in metastasis. Simultaneous targeting of factors regulating CSCs and TME, along with standard of care therapies, proves a better strategy to tackle CSC heterogeneity and their adaptation for metastatic disease. Further approaches impacting CSCs offer a promising avenue for enhancing the effectiveness of cancer therapeutics and discovering new anti-metastatic drug candidates.</p>