Epstein-Barr virus (EBV) DNA in blood is associated with many diseases, though most often it is not linked to any disease. EBV DNA can be measured in whole blood, PBMCs, serum, or plasma. Using the most sensitive assays, viral DNA can be detected in PBMCs in nearly all individuals who have been infected. Among organ transplant recipients, higher EBV DNA copy numbers in PBMCs may reflect the degree of immunosuppression and could help guide pharmacologic management. In patients with EBV-PTLD, treatment with rituximab or other anti-B cell therapies typically eliminates measurable EBV DNA in PBMCs, even when the disease continues to progress—making further PBMC measurements of limited value. In other settings, such as HIV associated lymphoma, nasopharyngeal carcinoma (NPC), or Hodgkin lymphoma (HL), EBV DNA levels in PBMCs do not appear useful for diagnosis or monitoring. Measurement of viral DNA in cell-free (CF) DNA is fundamentally different from measurement in PBMC or whole blood, as EBV DNA is generally undetectable in CF DNA in most seropositive individuals without EBV associated disease. In NPC and HL, evidence suggests that CF EBV DNA typically originates from tumor cells and is not packaged in virions. Persistence of CF DNA correlates closely with residual tumor presence. In NPC and NK/T cell lymphoma (NK/TCL), CF DNA assays are now commonly used for tumor monitoring. This is not yet standard in EBV-positive HL but represents a promising area for further research. EBV DNA is also assayed in whole blood in many clinical settings. This approach can detect high copy numbers in both cellular and CF compartments with minimal processing, but it obscures compartment-specific differences. Studies of EBV DNA fragmentomics and methylation in plasma offer new insights into tumor presence and potentially tumor type.