Mesenchymal stem cells (MSCs) possess the potential for use in cell-based therapy for repair of myocardial injury. The therapeutic potential of MSCs is based on the capacity of MSCs to differentiate into cardiac tissue and release paracrine factors. However, a major problem in the clinical application of MSC-based therapy is the poor viability of transplanted MSCs at the site of graft due to harsh microenvironment conditions, such as ischemia and/or anoikis. Ischemia after myocardial infarction (MI) and interaction of MSCs with their niche is associated with increased production of reactive oxygen species (ROS). ROS hinder cell adhesion and induce detachment of cells, which induces anoikis signals in implanted MSCs. Therefore, strategies to regulate oxidative stress following the implantation of MSCs are therapeutically attractive. In this review, we first describe ROS as a major obstacle in MSC-based therapy and focus on manipulation of implanted MSCs to reduce ROS-mediated anoikis.