The genetic profiling of patient material has yielded reliable prognostic biomarkers that are paramount for early detection, diagnosis and assessment of effective therapy. One drawback is that patient tissue is not always available or accessible without conducting timely and painful procedures. The presence of small genetic elements called ‘microRNAs’ in extracellular vesicles (EV) or stably bound to proteins in patient biofluids opens unique possibilities for using such circulating RNAs as easily accessible genetic biomarkers. Our laboratory uses multiple strategies for development of ‘liquid biopsy’ tests that should enable non-invasive diagnosis of cancer in the future, for instance by a simple blood test. We are using similar strategies in severe autoimmune patients with chronic inflammation and discovered a link between EV physiology (exosomes), Epstein Barr virus infection and antiviral immunity. For these studies we use the latest high-throughput next-generation sequencing techniques to unravel the complete small RNA landscape of exosomes. We have found fundamental differences between small RNAs in tissues/cell when compared to exosomes, pointing to a function outside the cell in which they were produced. Currently we investigate the possibility that small distinctions in extracellular small RNA content maybe applicable for non-invasive disease monitoring, primarily by isolation of exosomes from patient blood and urine (van Eijndhoven et al., 2016).