SUMMARY Finite element analysis has become an indispensable tool for research and discovery in the biomedical sciences. Historically, the lack of an open software environment that was tailored to the needs of the field hampered research progress, dissemination of research and sharing of models and results. To address these issues, we developed the FEBio software suite, a FE framework designed specifically for analysis in biomechanics and biophysics, during our first funding period (2007-2011). FEBio employs mixture theory to account for the multi- constituent nature of biological tissues and fluids, unifying the classical fields of irreversible thermodynamics, solid mechanics, fluid mechanics, mass transport, chemical reactions and electrokinetics. During the second funding period (2012-2016), we implemented chemical reactions between constituents of a mixture and we broadened the target audience for FEBio by developing a plugin environment that made it easy to add features or interface other software with FEBio. During our third funding period (2016-2020), we developed a novel FE framework for simulation of compressible and incompressible CFD, extended this framework to enable analysis of FSI (Fluid-Structure Interaction) problems, and we enhanced algorithmic, analysis and numerical capabilities in FEBio by implementing efficient iterative linear solvers and preconditioners, new nonlinear solution strategies, and adaptive meshing. In this competing continuation application, we propose three aims: 1) Formulate and implement a computationally efficient damage and fatigue failure framework for fibrous tissues; 2) Extend our multiphysics algorithms to solute transport and reactions in fluid domains, and tissue growth and remodeling in fluid domains and at their interfaces with multiphasic domains; 3) Integrate the use of image data through our entire simulation pipeline, from model setup to model validation. These new capabilities will expand the applicability of FEBio to new fields of biomedical research, increasing our user base and facilitating scientific advancement.