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, the development of new inhibitors was promoted. This led to the second-generation inhibitors dasatinib, nilotinib, and bosutinib. Despite all achieved improvements, 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 USA and in July 2013 in the European Union. The safety data of these trials particularly revealed a dose-dependent, increased risk for serious arterial occlusive events under treatment with ponatinib. Further trials investigate optimized dosing schemes to reduce side effects while maintaining clinical activity in CML and evaluate potential activity of the drug in 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 the pan-resistant T315I mutation. Ponatinib should be used catiously with respect to increased cardiovascular risk. Despite previous TKI failure, chronic-phase CML patients can achieve sustained remissions using this drug, offering an important addition to therapeutic options in the treatment for CML.