The key role of cancer stem cells (CSCs) in tumor development and therapy resistance makes them essential biomarkers and therapeutic targets. Numerous agents targeting CSCs, either as monotherapy or as part of combination therapy, are currently being tested in clinical trials to treat solid tumors and hematologic malignancies. Data from ongoing and additional clinical trials testing novel approaches to target tumor stemness-related biomarkers and pathways may pave the way for further clinical development of CSC-targeted treatments and CSC-guided selection of therapeutic regimens. In this concise review, we discuss recent progress in developing CSC-directed treatment approaches, focusing on clinical trials testing CSC-directed therapies. We also consider the further development of CSC-assay-guided patient stratification and treatment personalization.