In recent years, cisplatin has found wide application in different types of cancer. Among the different platinum compounds, cisplatin was found to be able to cross the cell membrane due to its simple chemical structure and, form adducts with DNA, to cause cell death. The removal of these adducts is mediated mainly by the excision repair cross complementing group 1 (ERCC1) protein of the nucleotide excision repair (NER) system whose activity affects tumor response. However, the use of cisplatin may be burdened by an acquired resistance due to the combination of different mechanisms. The purpose of this manuscript is to discuss the mechanisms of cytotoxicity and resistance to cisplatin.