Large cell change (LCC) is a noncommittal term used today to indicate liver cell dysplasia of the large cell type. Dysplasia was deleted from the original definition because not enough evidence has been collected over time to support premalignancy. LCC is a microscopically well-defined lesion, usually found in cirrhosis, whose origin, natural history, and fate are still debated. Different morphologic, phenotypic, molecular and clinical studies have been performed to address the issue of the dysplastic versus reactive nature of this lesion. The aim of this review is to critically evaluate the contributions to the topic and to underline that the heterogeneity of the lesion is an important issue to be taken into account for our biological understanding of it. While LCC has important morphologic analogies in experimental liver carcinogenesis, no comparable lesions are known in solid non-liver parenchymal human tissues that morphologically feature dysplasia, but in which it is uncertain whether the lesions are reactive or preneoplastic. The debate over the lesion may be useful in learning the actual limits of morphology and how additional information can be gained by looking inside the cells.