Densely ionizing radiation has always been a main topic in radiobiology. In fact, alpha-particles and neutrons are sources of radiation exposure for the general population and workers on nuclear power plants. More recently, high-energy protons and heavy ions attracted a large interest for two applications: hadrontherapy in oncology, and space radiation protection in manned space missions. For many years, studies concentrated on measurements of the relative biological effectiveness (RBE) of the energetic particles for different endpoints, especially cell killing (for radiotherapy) and carcinogenesis (for late effects). More recently though, it has been shown that densely ionizing radiation elicits signalling pathways quite distinct from those involved in the cell and tissue response to photons. The response of the microenvironment to charged particles is therefore under scrutiny, and both the damage in the target and non-target tissues are relevant. The role of individual susceptibility in therapy and risk is obviously a major topic in radiation research in general, and for ion radiobiology as well. Particle radiobiology is therefore now entering into a new phase, where beyond RBE the tissue response is considered. These results may open new applications both for cancer therapy and protection in deep space.