Abstract Helium ion beam therapy for the treatment of cancer was one of several developed and studied particle treatments in the 1950s, leading to clinical trials beginning in 1975 at the Lawrence Berkeley National Laboratory. The trial shutdown was followed by decades of research and clinical silence on the topic while proton and carbon ion therapy made debuts at research facilities and academic hospitals worldwide. The lack of progression in understanding the principle facets of helium ion beam therapy in terms of physics, biological and clinical findings persists today, mainly attributable to its highly limited availability. Despite this major setback, there is an increasing focus on evaluating and establishing clinical and research programs using helium ion beams, with both therapy and imaging initiatives to supplement the clinical palette of radiotherapy in the treatment of aggressive disease and sensitive clinical cases. Moreover, due its intermediate physical and radio-biological properties between proton and carbon ion beams, helium ions may provide a streamlined economic steppingstone towards an era of widespread use of different particle species in light and heavy ion therapy. With respect to the clinical proton beams, helium ions exhibit superior physical properties such as reduced lateral scattering and range straggling with higher relative biological effectiveness (RBE) and dose-weighted linear energy transfer (LET_d) ranging from ∼4 keV μm⁻¹ to ∼40 keV μm⁻¹. In the frame of heavy ion therapy using carbon, oxygen or neon ions, where LET_d increases beyond 100 keV μm⁻¹, helium ions exhibit similar physical attributes such as a sharp lateral penumbra, however, with reduced radio-biological uncertainties and without potentially spoiling dose distributions due to excess fragmentation of heavier ion beams, particularly for higher penetration depths. This roadmap presents an overview of the current state-of-the-art and future directions of helium ion therapy: understanding physics and improving modeling, understanding biology and improving modeling, imaging techniques using helium ions and refining and establishing clinical approaches and aims from learned experience with protons. These topics are organized and presented into three main sections, outlining current and future tasks in establishing clinical and research programs using helium ion beams—A. Physics B. Biological and C. Clinical Perspectives.