ABSTRACT. Radiotherapy can be delivered with photons or charged particles. Particle therapy includes treatment with different types of ions, such as protons, helium, carbon or oxygen ions having different linear energy transfer (LET). In contrast to conventional photon therapy, all ion beam treatments feature the so-called Bragg peak resulting in highly conformal tumor irradiation and greater normal tissue sparing. Heavier charged particles, such as helium, carbon and oxygen ions, result in improved tumor targeting capability due to their reduced lateral scattering. Additionally, carbon and oxygen ions offer biological advantages untapped by lower LET particles. One of the major differences between carbon/oxygen ions and lighter particles is their larger biological effectiveness in cell killing. This made them a prime candidate for treating tumor radio-resistant to conventional photon radiotherapy. This increase in efficiency is due to their higher LET which induces more complex, non-repairable, DNA damage. For challenging tumors with poor prognosis (e.g., pancreas and glioblastoma), in particular, novel approaches in particle therapy should be clinically introduced aiming to maximize tumor targeting in terms of biological dose and dose-averaged LET while maintaining a low toxicity profile of the normal tissue. These biophysical advantages have been only in part exploited in clinical practice. In this contribution, clinical/pre-clinical novel approaches in particle therapy will be presented. Technological, biophysical and biological innovations will be outlined such as multi-ion, heavy ion arc, FLASH radiotherapy and biologically advanced optimization approaches aiming to substantially improve in the next decades the clinical advantages of heavy ions over conventional photon therapy.