Interpretation of intestinal mesenchymal lesions is simplified merely by knowing in which anatomic layer they are usually found. For example, Kaposi sarcoma is detected on mucosal biopsies, whereas inflammatory fibroid polyp is almost always in the submucosa. Gastrointestinal stromal tumours (GIST) are centred generally in the muscularis propria. Schwannomas are essentially always in the muscularis propria. Knowledge of the favoured layer is also most important in interpreting colon biopsies, as many mesenchymal polyps are encountered in the colon. Herein we discuss several mesenchymal lesions and point out some diagnostic pitfalls.