Cardiac hypertrophy is a response of the heart to a wide range of extrinsic stimuli, such as arterial hypertension, valvular heart disease, myocardial infarction, and cardiomyopathy. Although this process is initially compensatory for an increase workload, its prolongation frequently results in congestive heart failure, arrhythmia, and sudden death. Cardiac hypertrophy is associated with an increase in glucose utilization and a decrease in fatty acid oxidation. It is unclear at present, however, which consequences might result from impaired oxidation of fatty acids in the heart, but several studies have demonstrated that substrate utilization is important in the pathogenesis of cardiac hypertrophy. Here we will focus on the effects of cardiac hypertrophy on the activity of Peroxisome proliferator-activated receptors (PPARs), ligand-activated transcription factors that regulate the expression of genes involved in fatty acid uptake and oxidation, lipid metabolism and inflammation. Interestingly, activation of the Nuclear Factor (NF)-κB signaling pathway, which is one of the most important signal transduction pathways involved in the hypertrophic growth of the myocardium, may suppress the activity of the PPARs, affording a link between cardiac hypertrophy and the fall in fatty acid oxidation in the hypertrophied heart. As a result, inhibition of NF-κB activation during cardiac hypertrophy may also ameliorate cardiac fatty acid oxidation, achieving a better improvement in the prevention or inhibition of this pathological process.