This article provides an overview of the histopathologically defined nonneoplastic and neoplastic entities involved in submucosal lesions (SMLs) of the gastrointestinal tract, particularly those in the upper gastrointestinal tract. The gross appearance and the histomorphological and cytomorphological features of the most frequent SMLs are described, including gastrointestinal stromal tumor (GIST), leiomyoma, lipoma, carcinoid, granular-cell tumor, glomus tumor, schwannoma, submucosal metastases, Brunner's gland hamartoma, pancreatic rests, and cysts. The current state of important technical aspects of biopsy processing and the role of histology and cytology in the diagnosis of SMLs are discussed.