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Cancer stem cells (CSCs) are a dynamic population of tumor cells characterized by long-term self-renewal, high tumorigenicity, resistance to conventional therapies such as radio- and chemotherapy, and capacity to recapitulate the tumor heterogeneity. Similar to other tumor cells, CSCs need to carry critical mutations and epigenetic changes to acquire their aberrant phenotype. Confirmed in various hematologic and solid malignancies, the critical need to deepen our understanding of CSC biology, including identification of CSC biomarkers, and develop novel CSC-targeted therapies has been clearly recognized. Here, we review the L1 cell adhesion molecule (L1CAM) as a CSC-associated biomarker in ovarian cancer. Furthermore, we inform on the promising potential of anti-L1CAM radioimmunotherapy with ¹⁶¹Tb as a novel CSC-targeted therapeutic approach to overcome CSC radioresistance in comparison to ¹⁷⁷Lu.