It is shown in this work that the manufacturing process, sterilization and aging environment play a critical role on the fatigue threshold and crack propagation rates in medical grade ultra high molecular weight polyethylene (UHMWPE). Two current manufacturing methods were evaluated for each material sample : compression molding and ram extrusion. The role of notch orientation relative to the extrusion direction was investigated in order to elucidate the effect of polymer microstructure on the fatigue fracture behavior of UHMWPE. In order to understand the role of post-sterilization aging, fatigue specimens were sterilized by gamma-radiation and aged in an air to simulate shelf aging or in a hydrogen peroxide to mimic a highly oxidative environment. Non-sterile material was used as a control for all studies. Understanding the factors which affect the threshold and fatigue crack propagation behavior of UHMWPE is crucial for the structural integrity of total joint replacements as polymer debris related to cyclic loading of the polyethylene inserts currently limits the life of orthopedic implants. It is found in this work that microstructure and orientation significantly affect the near threshold regime of UHMWPE. Compression molded and extruded polyethylene with notches oriented perpendicular to the extrusion axis offer the greatest resistance to fatigue crack propagation. Further, it is shown that gamma-radiation and oxidative aging are highly detrimental to fatigue threshold and crack propagation resistance. The findings from this study have important implications for the fatigue behavior of orthopedic grade UHMWPE as well as other semicrystalline polymers.