The immune system plays a critical role in tumor surveillance and cancer prevention. However, some cancer cells can evade immune destruction by acquiring the ability to inhibit immune checkpoint regulatory pathways and suppress anti-cancer immune responses. In recent years, the immune checkpoints took center stage in cancer immunotherapy and several promising strategies, based on the intervention in immune checkpoint-regulated pathways, have been designed in order to overcome mechanisms of immunosuppression. Clinical studies, using anti-inhibitory immune checkpoint-receptor antibodies, demonstrated durable clinical responses even in patients with advanced cancer. However, the clinical benefit was limited to a subset of cancer patients. Furthermore, the immune checkpoint therapy, which unleashes the immune system in order to augment the anti-cancer immune response, also increases the incidence of autoimmune diseases and induces an array of immune-related adverse effects. Here we briefly discuss some of the pros and cons of immune checkpoint-directed immunotherapy.