The pathological progression following myocardial infarction is very complex and involves a number of cell populations including cells localized within the heart, as well as cells recruited from circulation and other tissues that participate in inflammatory and reparative processes. These cells, with their secretory factors, have pleiotropic effects that depend on the stage of inflammation and regeneration. Excessive inflammation leads to enlargement of the infarction site, pathological remodeling and eventually, heart dysfunction. Stem cell therapy is considered a promising approach in treating coronary heart disease including myocardial infarction. However, harsh conditions at the site of injury, including hypoxia, oxidative and inflammatory stress, increased fibrosis and insufficient angiogenesis, and in some cases, immunological response or incompatibility, are detrimental to stem cell survival. To overcome the complexity and deficiencies of stem cell therapy, drug delivery systems are being investigated because they offer a controlled and sustained release of bound growth factors and cytokines. Moreover, targeted delivery of stem cells preconditioned with hypoxia and/or oxidative/inflammatory stimuli or pre-differentiated cells in combination with controlled release of immunomodulatory and wound healing factors will treat myocardial infarction more effectively than the transfer of factors alone, by reducing the infarct size and inflammation, and generating more functional cardiac tissue.