Myalgic Encephalomyelitis (ME) and Chronic Fatigue Syndrome (CFS) are subject to controversy. Although ME and CFS are often considered to be to be synonymous, the case criteria for ME and CFS define two distinct diseases with partial overlap. ME, recognized as a new clinical entity in the 1950’s, is characterized by distinctive muscular, neurological and autonomic symptoms. In contrast the core feature of CFS, introduced in 1988 and redefined in 1994, is chronic fatigue. Some researchers consider CFS to be equivalent to (incapacitating) chronic fatigue (CF). After the introduction of CFS, other criteria for ME, ME/CFS, CFS and CF were introduced and used in research studies, creating obfuscation and controversy. The use of various diagnostic criteria has hampered effective research into ME and CFS. Next to the various diagnostic criteria, the assessment of symptoms is almost always based on questionnaires and subjective measures, e.g. physical functioning. Due to their nature subjective measures are incomparable over time and between patients. Moreover subjective measures introduce a significant risk of bias, for example due to researcher allegiance, the Hawthorne effect, and buy-in effects. Despite the fact that ME and CFS (subclasses) lack a clear etiological explanation (yet), the symptoms can and should be assessed by objective test measures, since subjective measures are ambiguous, incomparable and minimize the risk of bias. Objective test measures can also confirm the seriousness of both ME and CFS. To resolve the diagnostic issues in research studies and clinical practice, a clear distinction between ME and CFS (not ME), based on the original criteria, is crucial. Although the use of objective test methods is more expensive and time-consuming and severe cases cannot be subjected to these tests, considering the (scientific) confusion originating from the use of subjective measures it is essential to assess the symptoms of patients objectively both in clinical practice and research settings.