Despite advances in our knowledge of celiac disease, the most current and authoritative recommendations conclude that diagnosis requires at least four biopsy specimens to be taken from the duodenal area. These recommendations are based on the perception that classic endoscopic markers are not adequate to target biopsy sampling to sites of villous damage in the duodenum. In the past few years, newly developed procedures and technologies have improved endoscopic recognition of the duodenum. These advances make possible the real-time recognition of the duodenal villous pattern during an upper endoscopy procedure, and thereby have the potential to optimize diagnostic accuracy. It is, therefore, reasonable to hypothesize that upper endoscopy might have a more incisive role in the diagnosis of celiac disease than merely providing a means of obtaining biopsy specimens for histological analysis. This Review highlights the new technologies in the field of upper endoscopy that could be helpful for the diagnosis of celiac disease, including the water-immersion technique, chromoendoscopy, high-resolution magnification endoscopy, optimal band imaging, optical coherence tomography and confocal endomicroscopy.