Aortic valve disease (AVD) and aortopathy are associated with substantial morbidity and mortality, representing a significant cardiovascular healthcare burden worldwide. These mechanobiological structures are morphogenetically related and function in unison from embryonic development through mature adult tissue homeostasis, serving both coordinated and distinct roles. In addition to sharing common developmental origins, diseases of the aortic valve and proximal thoracic aorta often present together clinically. Current research efforts are focused on identifying etiologic factors and elucidating pathogenesis, including genetic predisposition, maladaptive cell-matrix remodeling processes, and hemodynamic and biomechanical perturbations. Here, we review the impact of these processes as they pertain to translational research efforts, emphasizing the overlapping relationship of these two disease processes. The successful application of new therapeutic strategies and novel tissue bioprostheses for AVD and/or aortopathy will require an understanding and integration of molecular and biomechanical processes for both diseases.