At the site of the primary tumour, differentiated cancer cells and proliferating clusters of CSCs are subjected to immune cells clearance, instead CSCs that enter in a quiescent state are hidden. Isolated quiescent CSCs can enter the bloodstream and, evading the surrounding immune cells, are able to exit from dormancy and colonize the metastatic site. Metastatic outbreak can occur thanks to CSC plasticity and the acquisition of new immune evasive mechanisms. Like other types of treatments, CSCs are also refractory to immunotherapies leading to tumour relapse. These resistant cells overexpress key antigens or metabolic vulnerabilities that can be targeted by newer CSCs-specific immunotherapies or drugs directed to CSCs-associated pathways. Immunotherapies could be combined with targeted CSCs agents to both debulk the original tumour and eradicate any emerging resistant cells. However, the optimal timing, sequence and combination of these CSCs-specific, immune-based therapies requires further studies.