In summary, fatty acids are not only essential as sources of substrate for energy production, but individual fatty acids serve as signaling molecules for the induction of multiple different pathways for cellular function. Understanding the differential effects of specific lipid species on these downstream pathways is critical for understanding the basis of cellular lipotoxicity and, in turn, the pathogenesis of organ dysfunction in diseases such as diabetes. The data from Lockridge et al. (5) have provided important new insights into the effects of saturated and unsaturated fatty acids in mature cardiac myocytes at the level of gene expression. Additional studies to confirm the actual effect on cellular function will be important. Such studies might include evaluation of fatty acid oxidation rates, measurement of reactive oxygen species, and evaluation of ER and mitochondrial integrity after exposure to different fatty acids. In the long term, rescue strategies aimed at overexpression of specific gene targets that appear more cardioprotective or knockdown of those that are cardiotoxic may help guide potential therapies.