Cisplatin-based chemotherapies are the mainstay of several forms of cancer treatment both in adults and children, but their use may cause a plethora of side effects. Their high capacity to generate adducts with DNA accounts for their anticancer action but also for the side effects. However, that mechanism alone is not enough to completely explain their actions, especially on non-proliferative tissues, and cell damage derived from increased reactive oxygen species (ROS) production is a key mechanism involved in adverse reactions. Major side effects of cisplatinbased treatments may account for acute morbidity and even mortality during cancer treatment. They include nephrotoxicity, myelosuppression, cardiotoxicity, and hepatotoxicity, which may also lead to suspension or decreased dosage of cisplatin, which can ultimately compromiseoncologic long-term survival. Minor side effects include ototoxicity, hypogonadism, infertility and gastrointestinal dysfunction, among others. These effects are not normally associated with increased mortality, but they can decrease quality of life of cancer survivors. To date there are limited options to prevent cisplatin-based side effects and most interventions have a symptomatic aim or a discrete clinical efficacy. Efforts are currently directed to 1) optimize current intervention protocols and the therapeutic approach to adverse effects, 2) the application of new generation platinum-compounds, and 3) the development of innovative prophylactic strategies, which can hopefully reduce the side effects, but clinical data is still lacking.