In our genome-wide survey of gene expression in human peripheral blood cells using both an expressed sequence tag (EST) and a microarray hybridization approach, we identified the expression of a large proportion (approximately 80%) of the genes encoded in the human genome. Comparison of the peripheral blood transcriptome with genes expressed in nine different human tissue types revealed that expression of over 80% was shared with any given tissue. We also sought to determine whether those gene transcripts undetected by these methods were also expressed in peripheral blood cells. Using reverse-transcriptase-polymerase chain reaction, we detected additional tissue-specific gene transcripts including beta-myosin heavy chain (heart specific) and insulin (specific to pancreatic islet beta cells), in circulating blood cells. Arguably, the detection of low levels of tissue-specific transcripts could be considered products of "illegitimate" transcription; however, our study also demonstrates that environmental conditions affect the transcriptional regulation of insulin in the peripheral blood. We thus hypothesize that blood cells can act as sentinels of disease and that we could capitalize on this property of blood for the diagnosis/prognosis of disease (the "Sentinel Principle"). Peripheral blood is an ideal surrogate tissue as it is readily obtainable, provides a large biosensor pool in the form of gene transcripts, and response to changes in the macro- and micro-environments is detectable as alterations in the levels of these gene transcripts.