Heart disease is the leading cause of death in the world and cellular cardiomyoplasty is an emerging therapeutic option to repair damaged myocardium. Muscle-derived stem cells (MDSCs) have been shown to have an improved regenerative capacity in bone, cartilage, and skeletal muscle when compared to myoblasts. After implantation into ischemic hearts, MDSCs display high levels of engraftment, induce neoangiogenesis, prevent cardiac remodeling, and elicit significant improvements in cardiac function. Notably, diversity in MDSC behavior has been associated with innate sex-related differences in skeletal muscle, bone, and cartilage. These results suggest that differences in inherent stem cell characteristics, including sex and age, could account for some of the outcome variability noted in clinical trials. Therefore we examined the effect of sex-related differences of MDSCs in cardiac repair. Transplantation of both cell sexes significantly improved cardiac function in comparison to saline. We also found that with increasing age, the proliferation and differentiation abilities of MDSCs decreased while their survival under stress conditions and vascular endothelial growth factor (VEGF) secretion remained unchanged. Our in vivo study demonstrates that the age of MDSCs does not impact their regenerative capacity but increasing the age of the host leads to decreased repair, which implies that the majority of age-related decreases in repair are due to changes in the microenvironment. We then examined methods to improve the efficacy of cell transplantation via preconditioning strategies. We first investigated the effects of mechanical stimulation on increasing the secretion of VEGF, which plays a major role in effecting cardiac repair after cell transplantation. Mechanical preconditioning significantly increased VEGF secretion, angiogenesis, and cardiac function after myocardial infarction, suggesting that this method of cell preconditioning could increase therapeutic efficacy. Another major issue with cell therapy is low cell survival after implantation. We hypothesized that increasing the level of antioxidants in MDSCs prior to transplantation could increase survival and therefore improve functional cardiac repair. We found that antioxidant pretreatment increased cell survival, cardiac function, and angiogenesis, and decreased scar formation. These pretreatment strategies have the potential to significantly improve the efficacy of cell transplantation and enhance the outcomes of heart disease patients.