A miniaturized confocal microscope was developed that could be integrated in the distal tip of a conventional colonoscope. With this technique, denoted confocal endomicroscopy, subsurface analysis of the gut mucosa and in-vivo histology during ongoing endoscopy are possible in full resolution by point scanning laser analysis. The diagnostic spectrum of confocal endomicroscopy is expanding from screening and surveillance for colorectal cancer to Barrett's esophagus, Helicobacter pylori–associated gastritis, and gastric cancer. The new detailed images seen with confocal laser endomicroscopy allow a unique look on cellular structures at and below the surface of the gut. This review describes the optical and diagnostic possibilities of confocal laser endomicroscopy.