In clinical practice, a critical necessity nowadays is the detection of the so-called “minimal residual disease” (MRD) after primary surgery in highly metastatic tumors like melanoma. The MRD consists of residual tumor cells and micro-metastases, which could be dormant for years and even decades before they eventually re-emerge as solid metastases. At present, relapse detection is handled by the assessment of tumor markers. However, these markers are not always specific, and often they are not very sensitive because only sizable tumors secrete enough material for detection. Alternatively, imaging systems like the positron emission tomograph (PET) can detect tumors in the millimeter range, but are expensive and labor-intensive. In preliminary work, we discovered that certain markers in plasma-derived extracellular vesicles (pEVs) have the potential to predict and detect tumor relapse in melanoma. A remarkable finding was that circulating pEVs in cancer patients are released in abundance by the innate immune system, reacting very early and swiftly to the appearance of circulating and disseminated tumor cells. We hypothesize that this information can be used for diagnostic purposes because it can be used to assess the strength and efficacy of the immune response against the MRD.