Cardiovascular diseases remain the major cause of mortality and morbidity in the Western world. Heart failure is the most rapidly rising cardiovascular condition and is associated with high mortality. The etiology of heart failure is multiple, ranging from genetic cardiomyopathies to structural modifications to the heart following myocardial infarction or long-standing high blood pressure. Molecular system biology techniques (microarrays and proteomics) in combination with bioinformatics can now provide unique insights into the molecular mechanisms leading to heart failure. Both gene-gene and gene-environment interactions determine the specific phenotype and outcomes in this condition. The identification of these pathways also provides opportunities for the discovery of novel diagnostic and/or prognostic markers, and important therapeutic targets. How recent applications of genomics technologies depict a more complete portrait of molecular events in heart failure is summarized.