The matricellular protein osteopontin modulates cell-matrix interactions during tissue injury and healing. A complex multidomain structure of osteopontin enables it not only to bind diverse cell receptors but also to interact with various partners, including other extracellular matrix proteins, cytokines, and growth factors. Numerous studies have implicated osteopontin in the development and progression of myocardial remodeling in diverse cardiac diseases. Osteopontin influences myocardial remodeling by regulating extracellular matrix production, the activity of matrix metalloproteinases and various growth factors, inflammatory cell recruitment, myofibroblast differentiation, cardiomyocyte apoptosis, and myocardial vascularization. The exploitation of osteopontin loss- and gain-of-function approaches in rodent models provided an opportunity for assessment of the cell- and disease-specific contribution of osteopontin to myocardial remodeling. In this review, we summarize the recent knowledge on osteopontin regulation and its impact on various cardiac diseases, as well as delineate complex disease- and cell-specific roles of osteopontin in cardiac pathologies. We also discuss the current progress of therapeutics targeting osteopontin that may facilitate the development of a novel strategy for heart failure treatment.