The cardiac system has been a major target for intensive studies in the multi-scale modeling field for many years. Reproduction of the action potential and the ionic currents of single cardiomyocytes, as well as the construction of a whole organ model is well established. Still, there are major hurdles to overcome in creating a realistic and predictive functional cardiac model due to the lack of a profound understanding of the complex molecular interactions and their outcomes controlling both normal and pathological cardiophysiology. The recent advent of systems biology offers the conceptual and practical frameworks to tackle such biological complexities. This review provides an overview of major themes in the developing field of cardiac systems biology, summarizing some of the high-throughput experiments and strategies used to integrate the datasets, and various types of computational approaches used for developing useful quantitative models capable of predicting complex biological behavior.