Celiac sprue is a common lifelong disorder affecting 0.3-1% of the Western world and causing considerable ill health and increased mortality, particularly from lymphoma and other malignancies. Although high prevalence rates have been reported in Western Europe, celiac sprue remains a rare diagnosis in North America. Whether celiac sprue is truly rare among North Americans or is simply underdiagnosed is unclear, although serological screening of healthy American blood donors suggests that a large number of American celiacs go undiagnosed. Celiac sprue is an elusive diagnosis, and often its only clue is the presence of iron or folate deficiency anemia or extraintestinal manifestations, such as osteoporosis, infertility, and neurological disturbances. The challenge for gastroenterologists and other physicians is to identify the large population of undiagnosed patients that probably exists in the community and offer them treatment with a gluten-free diet that will restore the great majority to full health and prevent the development of complications. The advent of highly sensitive and specific antiendomysium and tissue transglutaminase serological tests has modified our current approach to diagnosis and made fecal fat and D-xylose absorption testing obsolete. A single small bowel biopsy that demonstrates histological findings compatible with celiac sprue followed by a favorable clinical and serological response to gluten-free diet is now considered sufficient to definitely confirm the diagnosis. We review the wide spectrum of celiac sprue, its variable clinical manifestations, and the current approach to diagnosis.