Clinical practice in psychiatry suffers from a lack of objective measures that could complement the clinical evaluation of the patient. The search for peripheral markers reflecting psychiatric disease state and trait has been under constant scrutiny for a few decades and numerous candidates have been tested based on several disease pathogenesis hypotheses. However, the results have often been of poor outcome or not replicable. Recent developments in proteomic and genomic approaches are expanding the number of testable hypotheses by some orders of magnitude and are allowing for the identification of patterns or signatures, rather than single markers, thus creating the premises for a paradigm shift in the search for biomarkers in psychiatry. A series of studies documenting the potential offered by large-scale transcription analyses and proteomic profiling in a number of psychiatric disorders are reported in this review. Specific applications of microarrays to CNS disorders to generate blood-derived disease signatures are discussed. Future progresses in genome- and proteome-wide investigations of peripheral samples and their integration with genetic and imaging studies will increase the chance of identifying non-invasive diagnostic tests providing clinicians with an integrated biological view of the psychiatric patients.