In this manuscript, we highlight the importance of understanding the risk factors associated with a high probability for chemotherapy resistance in patients with advanced penile cancer. We highlight the limitations of second-line cytotoxic chemotherapy or radiation, with very poor patients’ survival. Therefore, it is very important for clinicians caring for penile cancer patients to investigate molecular, immune, and human papillomavirus status in patients at risk of relapsed cancer after cisplatin-based chemotherapy. This is important to benefit the patients from immunotherapies with recent approvals based on high tumor mutational burden and to allow for enrollment on clinical trials that use targeted therapy, immune-based therapy, or HPV directed therapy.