Cardiac resynchronization therapy reduces morbidity and mortality in patients with symptomatic systolic heart failure (New York Heart Association class III or IV) and ventricular conduction delay. The current review focuses on how high-throughput technologies including gene expression profiling and proteomics have helped in our understanding of the pathophysiology of electromechanical dyssynchrony and the molecular mechanisms by which cardiac resynchronization therapy (CRT) exerts its beneficial effects. Comparing gene expression changes in early-activated anterior vs. late-activated lateral left ventricular myocardium in a large animal model of dyssynchronous heart failure, we demonstrated a profound effect of electromechanical dyssynchrony on the regional cardiac transcriptome, as changes in gene expression were primarily observed in the early-activated anterior left ventricular myocardium. This increase in regional heterogeneity of gene expression within the left ventricle was reversed by CRT. Specifically, CRT remodeled transcripts with metabolic and cell signaling function, which was corroborated by protein data. In addition, high-throughput or "omic" techniques also hold great promise to identify key pathways and biomarkers that are regulated differentially in CRT responders vs. nonresponders.