Total disc replacement (TDR) is expected to provide a more physiologic alternative to fusion. However, long-term clinical data proving the efficacy of the implants is lacking. Limited clinical data suggest somewhat of a disagreement between the in vitro biomechanical studies and in vivo assessments. This conceptual paper presents the potential biomechanical challenges affecting the TDR that should be addressed with a hope to improve the clinical outcomes and our understanding of the devices. Appropriate literature and our own research findings comparing the biomechanics of different disc designs are presented to highlight the need for additional investigations. The biomechanical effects of various surgical procedures are analyzed, reiterating the importance of parameters like preserving uncinate processes, disc placement and its orientation within the cervical spine. Moreover, the need for a 360° dynamic system for disc recipients who may experience whiplash injuries is explored. Probabilistic studies as performed already in the lumbar spine may explore high risk combinations of different parameters and explain the differences between "standard" biomechanical investigations and clinical studies. Development of a patient specific optimized finite element model that takes muscle forces into consideration may help resolve the discrepancies between biomechanics of TDR and the clinical studies. Factors affecting long-term performance such as bone remodeling, subsidence, and wear are elaborated. In vivo assessment of segmental spine motion has been, and continues to be, a challenge. In general, clinical studies while reporting the data have placed lesser emphasis on kinematics following intervertebral disc replacements. Evaluation of in vivo kinematics following TDR to analyze the quality and quantity of motion using stereoradiogrammetric technique may be needed.