Improvements in rehabilitation and prosthetic design are needed to help promote activities such as running that increase physical activity levels of individuals with lower extremity amputation (ILEA). However, effectively developing these improvements requires a detailed understanding of prosthetic and ILEA running biomechanics. Running-specific prostheses (RSPs) have been developed to improve running performance for ILEA runners, but altered running kinetics may still be necessary to accommodate for the loss of musculoskeletal function caused by lower extremity amputation. The few studies investigating ILEA running with RSPs focus on maximal performance, but our understanding of how ILEA using RSPs modulate kinetics to run at submaximal velocities remains limited. The purpose of this study was to characterize changes in kinetics and mechanical energy across a range of running velocities in ILEA wearing RSPs. This dissertation investigated six specific aims through six corresponding experiments that improve our knowledge of mechanical and anthropometric properties of RSPs and the kinetic profiles of ILEA running at submaximal velocities. Four common RSP designs were tested for mechanical and anthropometric properties. ILEA with unilateral transtibial amputations who wear RSPs and an able-bodied control group participated in the running experiments. Mechanical and anthropometric results indicated that RSP marker placement had little effect on joint kinetic estimations proximal to the prostheses, and trifilar pendulums can measure moments of inertia with <1% error. The running experiments provided the first 3D kinetic descriptions of ILEA running. The prosthetic limb typically generated lower peak kinetic parameters and 50% lower total mechanical work than the intact and control limbs, indicating a greater reliance on the intact limb. To counter the prosthetic limb deficiencies, ILEA increased stride frequencies compared to control subjects. Additionally, the prosthetic limb demonstrated prolonged periods of anterior ground reaction force to increase propulsive impulse and prolonged hip stance phase extension moments that generated increased hip concentric work. The data indicated that ILEA wearing RSPs run differently than able-bodied runners and use several adaptive mechanisms to run at the same velocity and to increase running velocity. These mechanisms are discussed and future directions of research are suggested.