Germ cell tumors (GCTs) account for the majority of testicular cancer cases occurring in men of young age and are divided into two main histologic groups, seminomas and non-seminomas. The introduction of cisplatin in the treatment of germ cell tumors was a breakthrough, classifying them among curable diseases. The identification of 3 subgroups of patients with non-seminomatous tumors (good-risk, intermediate and poor-risk), with different profiles concerning prognosis and response to treatment, supported clinical trials aiming to assess different treatment strategies and recommend the most effective and less toxic regimens. This review describes the toxic effects of therapy and the efforts aiming to overcome toxicity and improve treatment efficacy, focusing on the trials which form the basis of current standard treatment of non-seminomatous germ cell tumors.