This special issue will give the readers an insight on worldwide research on this topic. Different fields of interest are explored, describing the role of cancer stem cells, hypoxia, angiogenesis, immune system activation, DNA repair system, etc. in driving the biological effects induced by different types of treatment modalities and beams. Different experimental approaches are used, which cover the necessity of investigating basic medical physic and biological mechanisms, towards translational applications on preclinical and human models. The necessity to introduce biomarkers of normal tissues and tumor radiosensitivity into treatment planning is also discussed.