Cassiopea xamachana, the upside-down jellyfish, has become an emerging model to understand the dynamics of cnidarian photosymbiosis. Like reef-building corals, Cassiopea spp. engage in a nutritional endosymbiosis with algae of the family Symbiodiniaceae. The emergent model system is gaining traction at a time when understanding this symbiosis is a critical objective for coral reef conservation. The onset of symbiosis triggers production of medusae (strobilation) from the asexual sessile polyp stage (scyphistoma) to the sexual pelagic medusa stage (ephyra). Cassiopea are subject to thermal bleaching that leads to loss of photosymbionts. These life history traits make it a suitable system to study cnidarian–algal symbiosis establishment as well as its maintenance. The life cycle is now completed in the lab facilitating the study of the system anywhere in the world with both gametes and asexual polyps available year round for experimentation. We present protocols for husbandry, ecology, genetics, genomics, cell biology, microbiology and developmental studies that are used in the growing Cassiopea scientific community. Including recent breakthroughs in genetic tools (i.e. comparative and functional genomics, genome modification), this chapter outlines how Cassiopea has and will continue to be a valuable model for understanding basic biology.