Recent pre-clinical and clinical studies indicate that certain exogenous stem cells and biomaterials can preserve cardiac tissue after myocardial infarction. Regarding stem cells, a growing body of data suggests that the short-term positive outcomes are mainly attributed to paracrine signaling mechanisms. The release of such factors is due to the cell's ability to sense cardiac environmentally derived cues, though the exact feedback loops are still poorly understood. However, given the limited engraftment and survival of transplanted cells in the ischemic environment, the long-term clinical benefits of these therapies have not yet been realized. To overcome this, the long-term controlled delivery of bioactive factors using biomaterials is a promising approach. A major challenge has been the ability to develop timely and spatially controlled gradients of different cues, pivotal for the development and regeneration of tissues. In addition, given the complexity of the remodeling process after myocardial infarction, multiple factors may be required at distinct disease stages to maximize therapeutic outcomes. Therefore, novel smart materials that can sense the surrounding environment and generate cues through on demand mechanisms will be of major importance in the translation of these promising advanced therapies. This article reviews how the cardiac environment can mediate the release profiles of bioactive cues from cells and biomaterials and how the controlled delivery impacts heart regeneration.