The notion that gene expression signatures in blood can serve as biomarkers of disease states is not new. In the case of atherosclerosis, and coronary artery disease in particular, whether changes in gene expression in peripheral blood mononuclear cells reflects disease processes occurring in the vessel wall remains controversial. When comparing 15 studies that identified 706 differentially expressed genes, only 23 genes were replicated in 2 to 3 studies, at most. This low level of replication may reflect sample sizes too small to overcome heterogeneity in the response to disease. Genetic differences affect how each person responds to disease and what genes are altered. Recent studies with larger cohorts (over 5000 individuals) that considered the effect of common genetic variants still could not claim disease signature genes as biomarkers suggesting that even larger case-control studies will be required to achieve the required statistical power. On the other hand, out of 7 studies that identified 58 microRNAs, 12 were concordant in 2 or more studies, suggesting that microRNAs may be less affected by genetic differences and more accurately reflect the disease process. Here, we review the current state of knowledge on expression profiling and its utility for predicting coronary artery disease status and mortality.