The establishment of imatinib as the standard therapy for CML marked the beginning of a new era of treatment. Due to occurring intolerance and resistance against the drug, developing newer inhibitors was promoted. This led to the second-generation inhibitors dasatinib, nilotinib and bosutinib. Despite all achieved improvement, all first- and second-generation inhibitors are ineffective against the BCR-ABL T315I "gatekeeper" mutation. In order to overcome this issue and to further improve the inhibitory effect, the third-generation inhibitor ponatinib was developed. Various clinical trials have been launched to study the effect of ponatinib in the clinical setting. Based on positive phase 1 and phase 2 trials, ponatinib was approved for the second-line treatment of CML and Ph+ ALL in December 2012 in the United States and in July 2013 in the European Union. Further trials investigate the potential effect of ponatinib in kinase-dependent subgroups of other malignancies. In conclusion, ponatinib has proved to be a powerful BCR-ABL inhibitor, which exhibits clinical activity both in BCR-ABL wild-type and mutant CML, including activity against the T315I mutation. Despite previous TKI failure, chronic-phase CML patients can achieve sustained remissions using the novel drug, offering a new therapeutic option in the treatment for CML.