The prognosis of malignancies of the upper gastrointestinal tract is poor if early diagnosis is missed. Therefore, a rapid in vivo diagnosis of early cancer and premalignant lesions is highly important for successful therapy. Confocal laser endomicroscopy allows in vivo cellular and subcellular imaging at high resolutions during ongoing endoscopy. The first studies and clinical observations suggest a major role of this novel technique in the in vivo diagnosis of cancer of the esophagus and stomach and of precursor conditions, such as Barrett's esophagus, intestinal metaplasia of the stomach and Helicobacter pylori infection. Based on recent experiences from animal models, future studies will approach in vivo molecular imaging of human cancer.