Cardiovascular disease and its multiple sequelae comprise the leading cause of morbidity and mortality worldwide. Though overall mortality following myocardial infarction has improved substantially over the last half century, many patients will ultimately succumb to heart failure despite pharmacologic, revascularization, and reconstructive therapies. The gold standard treatments focus on pharmacologic management and macro-revascularization via percutaneous coronary intervention and/or coronary artery bypass graft. Yet these therapies fail to address the significant and pervasive microvascular malperfusion that occurs after myocardial infarction due to endothelial cell dysfunction and death and micro-occlusions. This microvascular malperfusion ultimately leads to cardiomyocyte injury and death, ventricular remodeling, and progressive functional deterioration. Targeted therapies via cardiovascular tissue engineering approaches offer an adjunct treatment to the gold standard via enhancing myocardial revascularization, repair and regeneration. To date, there has been modest and varied success with such approaches, likely due to limitations in mechanistic understanding and suboptimal delivery techniques. Thus, novel approaches to restore the microvasculature and repair myocardial tissue remain significant unmet needs. The Woo Lab studies endogenous mechanisms of myocardial angiogenesis, develops myocardial regeneration strategies, and translates novel molecular and biomaterial therapeutics for the prevention of heart failure. In this work, we aimed to elucidate and highlight the advantage of novel protein cytokine therapeutics delivered to the myocardium in translatable hydrogels for the treatment of myocardial ischemia. We examined the ability of an engineered dimeric fragment of hepatocyte growth factor (HGFdf) and an engineered variant of stromal cell-derived factor-1 (ESA) to stimulate cardioprotective functions in vitro on cardiac-relevant cell types including cardiomyocytes, endothelial progenitor cells, endothelial cells and fibroblasts. Additionally, we elucidated the advantage of delivering these cytokines in injectable hydrogels, which effectively prolonged their half-lives in vitro and in vivo, ultimately extending the therapeutic window. Harnessing lessons learned utilizing injectable hydrogels in small and large animal models motivated us to develop a novel, clinically translatable shear-thinning hydrogel, capable of being delivered through clinically relevant catheters. Further, due to the composition and structure of the hydrogel, we demonstrated biocompatibility and cell-signaling properties in addition to precise control over drug delivery via distinct cytokine release profiles. Finally, we translated this therapeutic hydrogel to small and large animal models of myocardial infarction, highlighting the clinical feasibility and potential of this hydrogel system to advance the field of cytokine therapy and hydrogels for the treatment of heart failure, potentially generating a significant impact on the treatment of patients afflicted with the most common cause of death worldwide.