Objectives: The main objective of the current dissertation is to establish a formal shape optimization procedure for a given bypass grafts end-to-side distal anastomosis (ETSDA). The motivation behind this dissertation is that most of the previous ETSDA shape optimization research activities cited in the literature relied on direct optimization approaches that do not guaranty accurate optimization results. Three different ETSDA models are considered herein: The conventional, the Miller cuff, and the hood models. Materials and Methods: The ETSDA shape optimization is driven by three computational objects: a localized collocation meshless method (LCMM) solver, an automated geometry pre-processor, and a genetic-algorithm-based optimizer. The usage of the LCMM solver is very convenient to set an autonomous optimization mechanism for the ETSDA models. The task of the automated pre-processor is to randomly distribute solution points in the ETSDA geometries. The task of the optimized is the adjust the ETSDA geometries based on mitigation of the abnormal hemodynamics parameters. Results: The results reported in this dissertation entail the stabilization and validation of the LCMM solver in addition to the shape optimization of the considered ETSDA models. The LCMM stabilization results consists validating a custom-designed upwinding scheme on different one-dimensional and two-dimensional test cases. The LCMM validation is done for incompressible steady and unsteady flow applications in the ETSDA models. The ETSDA shape optimization include single-objective optimization results in steady flow situations and bi-objective optimization results in pulsatile flow situations. Conclusions: The LCMM solver provides verifiably accurate resolution of hemodynamics and is demonstrated to be third order accurate in a comparison to a benchmark analytical solution of the Navier-Stokes. The genetic-algorithm-based shape optimization approach proved to be very effective for the conventional and Miller cuff ETSDA models. The shape optimization results for those two models definitely suggest that the graft caliber should be maximized whereas the anastomotic angle and the cuff height (in the Miller cuff model) should be chosen following a compromise between the wall shear stress spatial and temporal gradients. The shape optimization of the hood ETSDA model did not prove to be advantageous, however it could be meaningful with the inclusion of the suture line cut length as an optimization parameter.