Embryonic stem cells and induced pluripotent stem cells have the potential to be a renewable source of cardiomyocytes for use in myocardial cell replacement strategies. Although progress has been made towards differentiating stem cells to specific cell lineages, the efficiency is often poor and the number of cells generated is not suitable for therapeutic usage. Recent studies demonstrated that controlling the stem cell microenvironment can influence differentiation. Components of the extracellular matrix are important physiological regulators and can provide mechanical cues, direct differentiation and improve cell engraftment into damaged tissue. Bioreactors are used to control the microenvironment and produce large numbers of desired cells. This article describes recent methods to achieve cardiomyocyte differentiation by engineering the stem cell microenvironment. Successful translation of stem cell research to therapeutic applications will need to address large-scale cardiomyocyte differentiation and purification, assessment of cardiac function and synchronization, and safety concerns.