Cancers are caused by the sequential accumulation of alterations in genes that control the growth, differentiation, and other behaviors of cells. It has long been recognized that cancers are very heterogeneous pathologically, which is a reflection of the variable genetic lesions that give rise to the variety of lesions present in the gastrointestinal tract. Despite this complexity, certain types of genetic alterations are linked to specific pathologic lesions. This review summarizes the current understanding of the molecular pathogenesis of gastrointestinal neoplasia and provides explanations for some of the pathologic variability of lesions encountered by the endoscopist.