Transplantation of stem cells into the heart can improve cardiac function after myocardial infarction and in chronic heart failure, but the extent of benefit and of reproducibility of this approach are insufficient. Survival of transplanted cells into myocardium is poor, and new strategies are needed to enhance stem cell differentiation and survival in vivo. In this review, we describe how biomaterials can enhance stem cell function in the heart. Biomaterials can mimic or include naturally occurring extracellular matrix and also instruct stem cell function in different ways. Biomaterials can promote angiogenesis, enhance engraftment and differentiation of stem cells, and accelerate electromechanical integration of transplanted stem cells. Biomaterials can also be used to deliver proteins, genes, or small RNAs together with stem cells. Furthermore, recent evidence indicates that the biophysical environment of stem cells is crucial for their proliferation and differentiation, as well as their electromechanical integration. Many approaches in regenerative medicine will likely ultimately require integration of molecularly designed biomaterials and stem cell biology to develop stable tissue regeneration.