The broad repertoire of secreted trophic and immunomodulatory cytokines produced by mesenchymal stem cells (MSCs), generally referred to as the MSC secretome, has considerable potential for the treatment of cardiovascular disease. However, harnessing this MSC secretome for meaningful therapeutic outcomes is challenging due to the limited control of cytokine production following their transplantation. This review outlines the current understanding of the MSC secretome as a therapeutic for treatment of ischemic heart disease. We discuss ongoing investigative directions aimed at improving cellular activity and characterizing the secretome and its regulation in greater detail. Finally, we provide insights on and perspectives for future development of the MSC secretome as a therapeutic tool.