It has been postulated that the failing heart suffers from chronic energy starvation, and that the derangements in cardiac energy production contribute to the inevitable transition from compensated hypertrophy to decompensated heart failure. Although the existence of metabolic alterations is hardly disputed anymore, the molecular mechanisms driving this "metabolic remodeling" process and its significance for the development of cardiac failure are still open to discussion. Next to changes in mitochondrial function, the hypertrophied heart is characterized by a marked change in substrate preference away from fatty acids toward glucose. Several lines of evidence suggest that these metabolic adaptations are brought about, at least in part, by alterations in the rate of transcription of genes encoding for proteins involved in substrate transport and metabolism. Here, we present an overview of the principal metabolic changes and discuss the various mechanisms that are likely to play a role, with special emphasis on gene regulatory mechanisms. In addition, the significance of these changes for the etiology of heart failure is discussed.