Peripheral blood represents an attractive tissue source in clinical pharmacogenomic studies, given the feasibility of its collection from patients and its potential as a sentinel tissue to monitor perturbations of physiology in many disease states. The hypothesis is that the circulating blood cells monitor the physiological state of the organism and alter their transcriptome in response to this surveillance. However, the successful implementation of transcriptional profiling of peripheral blood cells in clinical trials represents a tremendous technical challenge for several reasons, including controlling the pre-analytical variables associated with sample processing and the interpretation of gene expression signatures generated from the complex mixture of cell types in blood. Multiple approaches for identifying transcriptomes in peripheral blood cells exist and each method is associated with significant advantages and disadvantages. Nonetheless, a growing number of studies are rapidly identifying transcriptional biomarkers in peripheral blood cells that may function as biomarkers of disease, evidence of pharmacodynamic effect, or even predictors of clinical outcomes and risk of toxicity. This review highlights the major approaches employed in global transcriptional profiling of peripheral blood cells and summarizes the available literature of initial studies in the growing field of hemogenomics. The overall purpose of the review is to focus on the development and application of technologies for the use of peripheral blood cells as a sentinel or surrogate tissue to measure disease state and drug response.