Impaired myocardial energy metabolism in cardiac hypertrophy and failure is characterized by decreased fatty-acid oxidation and increased glucose utilization. Mechanisms involving deactivation of peroxisome proliferator-activated receptor α/relinoid X receptor α (PPARα/ RXRα), and activation of chicken ovalbumin upstream promoter transcription factor (COUP-TF), and transcription factors Sp1 and Sp3, lead to decreased capacity for fatty acid utilization in hypertrophied hearts. Furthermore, impaired myocardial energetic status stimulates glucose uptake and glycolysis, which, in combination with the permissive effect due to decreased fatty acid oxidation, promotes increases in glucose utilization in hypertrophied hearts. Finally, shifting substrate utilization toward glucose is likely adaptive and has the potential to delay transition to heart failure.