Large gastric folds are seen in a great number of benign and malignant conditions. Diagnosis is a clinical challenge because the etiology may be extremely varied and standard biopsies are often inconclusive. The gastric wall is considered thickened at endosonography when it is more than 3.6 mm in width. Different diseases show different levels of infiltration of the gastric wall. When abnormalities involve the second layer only, benign conditions can be considered and standard endoscopic biopsies are often diagnostic. When abnormalities involve layers two and three, different diseases can be suspected, including Helicobacter pylori infection and lymphoma; in this case large-particle biopsy should be considered. When abnormalities involve layer four, malignancy should be strongly suspected even if standard or large-particle biopsies are negative. Endosonography, always in combination with fine-needle or guillotine-needle biopsy, should be able to rule out malignancies and to select the most appropriate treatment for each patient.