Children and adolescents with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) are more vulnerable to suffering comorbid depression and anxiety than their healthy peers and those with other chronic illnesses. However, for both research and clinical purposes, mental health screening in this population has relied mostly on questionnaires, which cannot enable a complex judgment about whether participants fulfill diagnostic criteria for psychiatric disorder, and may be confounded by overlapping symptoms of CFS/ME and depression and anxiety (e.g., fatigue, lack of energy, difficulties with insomnia or hypersomnia, and restlessness). Our research study aims to identify the prevalence of depression and anxiety disorders in a large cohort of children with CFS/ME using a semi-structured diagnostic interview and to evaluate the sensitivity and specificity of mental health screening questionnaires for use with this population. In this case study, we describe how we faced the challenge of interviewing children who are fatigued. We discuss the compromise between ensuring that research materials are sufficiently comprehensive to assess the Diagnostic and Statistical Manual of Mental Disorders, 5th ed., diagnostic criteria, while minimizing the risk that participation in the study could exacerbate fatigue, and thus lead to drop out or to recruiting a biased sample of those who are less severely affected by their illness. Input from a patient advisory group at the early stages to help with the design of the study was invaluable. Being flexible about where the interviews took place, offering regular breaks, and choosing only the most important sections of the diagnostic interview were important aspects of the design.