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Since the start of clinical operation in November 2009, state-of-the-art ion beam therapy with scanned proton and carbon ion beams is available at the hospital-based Heidelberg Ion Beam Therapy Center (HIT). Full clinical exploitation of the promised advantages of ion beam therapy can significantly benefit from accurate methods of calculation of the dose delivery and non-invasive in-vivo verification of the applied treatment. For this purpose, dedicated research has been performed at HIT in order to integrate Monte Carlo calculations into the clinical framework, as well as to pave the way towards utilization of a commercial PET/CT scanner next to the treatment rooms for post-radiation imaging of the irradiation-induced ß+-activity. This contribution will provide an overview of the performed activities with main emphasis on 1) the role of Monte Carlo to support treatment planning algorithms from basic data generation to an automated workflow of dose calculations of patient plans, and 2) the roadmap from first phantom studies to first clinical applications of PET/CT imaging after irradiation with proton and carbon ion beams. In particular, it will illustrate examples from the several patients whose treatment plans were recalculated with Monte Carlo prior to first beam delivery, and from the first patients whose treatments were successfully confirmed by post-activation studies. Despite the added benefits, post-radiation treatment verification suffers from intrinsic limitations such as biological clearance of the induced activity and patient repositioning, as deduced from repeated measurements. Therefore, an overview of ongoing investigations aiming to improve the PET methodology for optimal exploitation of the activity signal measured 5–8 minutes after scanned beam delivery will be given. [ABSTRACT FROM PUBLISHER]