Angela Alama, Anna Maria Orengo, Silvano Ferriniand Rosaria Gangemibriefly review different approaches to override the drug-resistance mechanisms of cancer initiating cells (CICs) and for increasing the efficacy of current cytotoxic treatments. They focus our attention to the new anti-CICs based therapies that have entered clinical trials. In addition, they discuss the possible role of CICs in tumor immune-escape as well as their targeting by immunotherapy strategies.