Bleeding of which the patient is unaware is the most common form of gastrointestinal blood loss, while that of unknown origin persisting or recurring after no source has been found at initial or primary endoscopy, or evident bleeding from an unidentified source represents the least common. Moreover, iron deficiency anemia, a common problem in clinical practice, most frequently originates from the gastrointestinal tract. The diagnostic approach to these apparently different clinical scenarios is actually very similar. In the present review, we summarize the characteristics of the tools employed in the diagnosis of these conditions, with a special emphasis on nuclear medicine techniques.