Future personalized medicine strategies for assessing an individual's health require, ideally, a noninvasive system that is capable of integrating numerous interactive factors, including gender, age, genetics, behavior, environment and comorbidities. Several microarray-based methods developed to meet this goal are currently under investigation. However, most rely on tissue biopsies, which are not readily available or accessible. As an alternative, several recent studies have investigated the use of human peripheral blood cells as surrogate biopsy material. Such studies are based on the assumption that molecular profiling of circulating blood might reflect physiological and pathological events occurring in different tissues of the body. This has led to the development of novel methods for identifying and monitoring blood biomarkers to probe an individual's health status. Here, we discuss the rationale and clinical potential of profiling the peripheral-blood transcriptome.