Penile carcinomas are rare in the USA, Europe and other industrialized countries [1]. In contrast, their incidence is significantly higher in some less developed countries in South America, Africa and Asia, accounting for as much as 10-20% of male cancers [2,3]. The annual incidence of penile squamous cell carcinoma (SCC) increases with age, with a median age of 68 years [4,5]. Many factors are known to increase the risk of developing a precursor lesion or a SCC of the penis, such as phimosis, HPV, HIV and tobacco exposure [6][7][8][9]. A number of medical conditions are also associated with an increased risk of developing penile cancer: a history of penile injury, tear, or chronic rash lasting one month or longer; a history of urethral structure, urinary tract infection or genital warts [8]. It is interesting to note that sexual orientation (heterosexual, bisexual/homosexual) is not a risk factor for penile cancer [9].The majority of penile cancers are diagnosed at a local stage (61%); these cancers are characterized by early locoregional spread with subsequent potential for distant dissemination [10]. Disseminated metastatic penile cancers are treated based on the localizations of the metastases, the symptoms of the patients and their performance status [11]. In general, for the treatment of metastatic penile cancer, systemic chemotherapy, radiation therapy or chemoradiation can be considered [12]. Given the rarity of penile cancer, there are no randomized clinical trials to define the preferred chemotherapeutical regimen [13,14].With the tsunami of checkpoint inhibitors during the last 3 years, these potent anticancer agents showed remarkable results in the management of different malignancies. During the last few years, checkpoint inhibitors were approved in melanoma, non-small-cell lung cancer, bladder cancer, squamous cell head and neck cancer, renal cell carcinoma and Hodgkin's lymphoma. They were tested in rare cancers where no strong standard of care treatment was present [15].We aimed in this paper to first describe the standard treatment of metastatic penile cancer. Given the fact that checkpoint inhibitors are demonstrating promising results in different malignancies, we then focused on their potential role in the management of this rare disease based on histology, risk factors and ongoing trials results.The rationale behind the use of checkpoint inhibitors in metastatic penile cancers In the absence of highly efficient therapies in the treatment of metastatic penile carcinoma, this rare tumor seems to be an interesting landscape for exploring checkpoint inhibitors. Different histologic, epidemiologic and therapeutic aspects encouraged researchers to test this drug in this malignancy. In fact, checkpoint inhibitors showed interesting results in virus-induced cancer, namely those related to HPV in SCC of the head and neck, the cervix and the anus [16]. This is mainly attributed to a specific immunologic profile probably related to a higher mutational load of these tumors and a higher expression of PD-...