Thymic mimetic cells are hybrids of medullary thymic epithelial cells and diverse peripheral cell types. They are important for imposition of self-tolerance and perform other functions similar to those of their peripheral counterparts. Following early histological observations of “misplaced” stromal cells in thymi from multiple species, mimetic cells were first molecularly investigated in mice. Recent studies have characterized mimetic cells in humans and zebrafish with high-resolution. Many mimetic cell types are conserved across species, although specialized subtypes as well as variable frequencies and levels of specialization are also apparent. Features of the human mimetic cell repertoire, such as the expanded nature of muscle mimetic cells with potential implications in myasthenia gravis and the similarity of tuft mimetic cells and thymic carcinomas, hint at their relevance in human disease. Here we review what is known about mimetic cells across diverse organisms. We discuss potential pressures shaping the composition of the mimetic cell repertoire within and across species, and highlight potential therapeutic applications in human disease.