The immune system has come to the forefront of cancer therapeutics in recent years with the success of immune blockade inhibitors in a variety of cancers whose list is increasing with a quick pace. Despite the efficacy of these drugs across a significant part of the cancer spectrum, responses are still seen only in a minority of patients, that implies that most patients are refractory or promptly develop resistance to these agents. Mechanisms of this resistance are important to decipher as this knowledge may lead to the introduction of additional therapies or manipulations to modulate resistance. The cancer stem cell theory stipulates that a minority of cancer cells in a given tumor are responsible for self-renewal and bulk tumor propagation. These cells, in most instances, are rare and less proliferative but give rise to highly proliferative progeny. In addition, they are, in general, resistant to therapies and endowed with metastatic potential through a process called EMT (Epithelial to Mesenchymal Transition). Cancer stem cells resistance to treatments may relate to inherent insensitivity to external apoptotic stimuli and, thus, may extend to immune therapies by inhibiting the actions of Cytotoxic T Lymphocytes (CTLs) in the tumor micro-environment. This paper examines available data on expression and regulation of immune co-modulatory (co-stimulatory and co-inhibitory) ligands on cancer stem cells in order to devise strategies to circumvent resistance.