The discovery that cancer cells actively and passively release their content into the blood stream has opened enormous opportunities for characterizing cancer cells without the need for surgery to access tumor tissue. Instead, a simple drop of blood is sufficient to detect and characterize cancer cells inside a patient’s body. The use of circulating DNA molecules has spurred this field, but the study of circulating RNA molecules also seems attractive with specific claimed advantages. To advance the extracellular RNA (exRNA) research field and deliver innovations in biomarker research with the ultimate goal to improve cancer patients’ outcome, I aim to address important open questions on the biology of tumor-derived exRNA in liquid biopsies, currently hampering the clinical implementation of exRNA biomarkers. More specifically, I aim to address in which subcompartment of the blood tumor-derived exRNAs primarily reside, how stable these molecules are in circulation and dynamically change upon treatment, and how changes in tumor burden levels during the patient’s disease course influence tumor exRNA detection. I will apply complementary sequencing- and PCR-based technologies to profile biomaterials from melanoma mice and rat models, as well as from melanoma patients. I put forward that the results of my project will be relevant for other cancer types as well.