As more detailed molecular information accumulates on the biology of the heart and other complex systems in health and disease, the need for new integrative analyses and tools is growing. Systems biology and bioengineering seek to use high-throughput technologies and integrative computational analysis to construct networks of the interactions between molecular components in the system, to develop systems models of their functionally integrated biological properties, and to incorporate these systems models into structurally integrated multi-scale models for predicting clinical phenotypes. This review gives examples of recent applications using these approaches to elucidate the electromechanical function of the heart in aging and disease.