Whole blood gene expression profiling has the potential to be informative about dynamic changes in disease states and to provide information on underlying disease mechanisms. Having demonstrated proof of concept in animal models, a number of studies have now tried to tackle the complexity of cardiovascular disease in human hosts to develop better diagnostic and prognostic indicators. These studies show that genomic signatures are capable of classifying patients with cardiovascular diseases into finer categories based on the molecular architecture of a patient's disease and more accurately predict the likelihood of a cardiovascular event than current techniques. To highlight the spectrum of potential applications of whole blood gene expression profiling approach in cardiovascular science, we have chosen to review the findings in a number of complex cardiovascular diseases such as atherosclerosis, hypertension and myocardial infarction as well as thromboembolism, aortic aneurysm, and heart transplant.