The heart is the most dynamic organ in the body and involves interactions among the rhythmic excitation of the cardiac conduction system and working myocardium, the active contraction of the heart muscle, and the mechanical interactions between the blood, the thick muscular walls, and the thin, flexible valve leaflets. This presentation will describe work to build comprehensive computational models of the heart that account for interactions between electrophysiology, mechanics, and fluid dynamics. Cardiac mechanics, fluid dynamics, and fluid-structure interaction (FSI) are simulated using the immersed finite element-difference method, an extension of the immersed boundary method for FSI models that include elastic bodies described using nonlinear continuum mechanics. Cardiac electrophysiology is described using a monodomain model of the whole heart that includes the atrial and ventricular myocardium, as well as major components of the specialized cardiac conduction system, including the sinoatrial node, Bachmann's bundle, the atrioventricular node, and the His–Purkinje network. Our cardiac electro-fluid-mechanical models build on our prior work simulating cardiac fluid dynamics in the human heart. We will demonstrate many of the key capabilities of our cardiac electro-fluid-mechanical modeling platform. The model generates physiological dynamics, including pressure-volume loops, valvular pressure-flow relationships, and vortex formation times that are in excellent agreement with clinical and experimental data. The model also captures realistic changes in cardiac output in response to changing loading conditions, recapitulating the well-known Frank–Starling mechanism. We investigate the impact of changes in cardiac mechanics resulting from modifications to the active strain model of muscle contraction. We also present initial results leveraging the capabilities of the full electro-fluid-mechanical model, including the effects of left and right bundle branch block on cardiac dynamics.