Radiation therapy has been successful in treating lung cancer patients, but its efficacy is limited by the inability to account for the respiratory motion during treatment planning and radiation dose delivery. Physics-based lung deformation models facilitate the motion computation of both tumor and local lung tissue during radiation therapy. In this dissertation, a novel method is discussed to accurately register 3D lungs across the respiratory phases from 4D-CT datasets, which facilitates the estimation of the volumetric lung deformation models. This method uses multi-level and multi-resolution optical flow registration coupled with thin plate splines (TPS), to address registration issue of inconsistent intensity across respiratory phases. It achieves higher accuracy as compared to multi-resolution optical flow registration and other commonly used registration methods. Results of validation show that the lung registration is computed with 3 mm Target Registration Error (TRE) and approximately 3 mm Inverse Consistency Error (ICE). This registration method is further implemented in GPU based real time dose delivery simulation to assist radiation therapy planning.