Symptom-based conditions such as chronic fatigue syndrome (CFS) and medically unexplained multi-symptom illness (MSI) are fairly common in the general population and are also important veteran's health concerns due to their higher frequency among U.S. veterans who served during the 1990-1991 Gulf War. CFS, MSI, and other symptom-based conditions are often associated with considerable morbidity due to fatigue, chronic pain, neurologic symptoms, and other symptoms that can impair the quality of life. This article discusses several important issues of methodology that arise in population studies of CFS and MSI. These include the exclusion criteria that have been used in population studies to define CFS-like illness and unexplained MSI, the potential for false positive and false negative assessments of illness status, the potential for sex differences, and the poorly understood natural history of these symptom-based conditions across the life span. As an empirical example of these methodology issues, we examined existing data from a 2005 follow-up survey. We found that 64.9% (762 of 1,175) of female Gulf War veterans and 53.4% (2,530 of 4,739) of male Gulf War veterans had 1 or more exclusionary medical conditions. The prevalence among veterans with one or more exclusionary medical conditions increased markedly by age among females and those with a low income.