The diagnosis of myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) is based on clinical criteria, yet there has been no consensus regarding which set of criteria best identifies patients with the condition. The Institute of Medicine has recently proposed a new case definition and diagnostic algorithm. To review methods to diagnose ME/CFS in adults and identify research gaps and needs for future research. MEDLINE, PsycINFO, and Cochrane databases (January 1988 to September 2014); clinical trial registries; and reference lists. English-language studies describing methods of diagnosis of ME/CFS and their accuracy. Data on participants, study design, analysis, follow-up, and results were extracted and confirmed. Study quality was dual-rated by using prespecified criteria, and discrepancies were resolved through consensus. Forty-four studies met inclusion criteria. Eight case definitions have been used to define ME/CFS; a ninth, recently proposed by the Institute of Medicine, includes principal elements of previous definitions. Patients meeting criteria for ME represent a more symptomatic subset of the broader ME/CFS population. Scales rating self-reported symptoms differentiate patients with ME/CFS from healthy controls under study conditions but have not been evaluated in clinically undiagnosed patients to determine validity and generalizability. Studies were heterogeneous and were limited by size, number, applicability, and methodological quality. Most methods were tested in highly selected patient populations. Nine sets of clinical criteria are available to define ME/CFS, yet none of the current diagnostic methods have been adequately tested to identify patients with ME/CFS when diagnostic uncertainty exists. More definitive studies in broader populations are needed to address these research gaps.