Biological systems are exceptionally complex. In particular, cancer progression and treatment present several challenges that require multi-scale modeling. In this talk, I briefly review practical and computational approaches in modeling the interaction of ionizing radiation with biological systems. Based on recent experimental data analysis, I present examples that the conventional mechanistic approaches fail to describe the observed RBE’s. I will discuss the possibilities in improving the current models and introduce a novel approach to enable studies the real-time DNA damage-repair pathway in the cell-survival biological endpoint in-silico to quantify the radiobiological effectiveness of photon beams, charged particles, and heavy ions. Specific goals for potential enhancements in therapeutic applications and treatment planning will be sketched. For illustration of the methodology, the predicted population of DSBs along the proton track with the highest occurrence frequency in the Bragg peak and a quantitative comparison demonstrating the agreement between theoretical predictions and more recently reported experimental data based on