Cardiac hypertrophy is a significant independent risk factor for increased mortality, comprising of maladaptive changes in cellular, molecular and metabolic processes that ultimately lead to heart failure. However, cardiac hypertrophy represents a continuum from physiological to compensatory to pathological hypertrophy, so that treatment modalities aimed to shift hypertrophy towards the physiological phenotype would represent an attractive therapeutic strategy. Many of the physiological changes caused by thyroid hormone (TH) treatment may provide direct benefit to the failing heart. Recent experimental studies have shown that TH rapidly activates pro-survival PKB/Akt-mTOR signaling pathways, thus providing cytoprotection and increasing synthesis of normal contractile proteins and metabolic enzymes. TH induces a normal physiological phenotype by binding to nuclear TH receptors that regulate expression of specific genes which promote cell survival and enhance contractile function. Physiological cardiac growth occurs with a coordinated angiogenic response that normalizes myocardial perfusion during hypertrophy, and recent studies support a significant role for TH and its endothelial cell surface integrin receptors and nuclear receptors in neovascularization during TH-induced hypertrophy. The present review examines these molecular mechanisms and intracellular signaling pathways activated in thyroid hormone-induced cardiac hypertrophy that support its therapeutic potential in the treatment of heart disease.