The tissue scale is an important spatial scale for modeling the human body. Tissue-scale biomechanical simulations can be used to estimate the internal muscle stresses and bone strains during human movement, as well as the distribution of force in muscles with complex internal architecture and broad insertion areas. Tissue-scale simulations are of particular interest for muscle structures where the changes in the shape of the structure are functionally important, such as the face, tongue, and vocal tract. Biomechanical modeling of these structures has potential to improve our understanding of orofacial physiology in respiration, mastication, deglutition, and speech production. Biomechanical simulations of the face and vocal tract pose a challenging engineering problem due to the tight coupling of tissue dynamics between numerous structures: the face, lips, jaw, skull, tongue, hyoid bone, soft palate, pharynx, and larynx. In this chapter, we describe our efforts to develop novel tissue-scale modeling and simulation techniques targeted to orofacial anatomy. We will also review our efforts to apply such simulations to reveal the biomechanics underlying orofacial movements.