Prevention of cardiovascular disease (CVD) remains a major health issue in the Western world. The diagnostic and therapeutic approach is currently based on risk factor assessment and treatment, which adequately predicts CVD at population level, but not at the level of a single individual. This may arise from the fact that the stage and activity of complex disease states are not likely to be captured by a single parameter or a small set of markers and thus may need a more complex representation. The aim of this review is to explore the possibility of pursuing the use of high-throughput gene expression profiling as a way to improve diagnosis, prognosis and monitoring of the disease. Novel chip-based techniques such as oligo- and cDNA microarrays can measure the abundance of thousands of mRNA transcripts in parallel and thus provide a comprehensive picture of the cell phenotype. Circulating white blood cells (WBCs), which are exposed to the systemic environment (including the risk factors) and are directly involved in the low-grade chronic inflammation related to CVD, have the potential to be used in this context to improve phenotyping of the patient. The paper reviews conceptual limitations in the use of risk factors and biomarkers, and shows the rationale beyond the possible use of circulating WBCs or subpopulations as representative cells to monitor systemic consequences of CVD. Methodological issues in performing microarray analysis of WBCs are also addressed, including controversies related to the choice of adequate cell populations and reference samples. Reproducibility and challenges occurring in the definition of a disease-specific gene panel are also discussed. The available proofs of principle from the literature presented in the last section of the review further support exploration of the application of circulating cell transcriptomics in CVD.