Abstract: Cassiopea jellyfish is the so called “upside-down” jellyfish due to an unique behavior among scyphozoans and it remains inverted position and sedentary throughout the majority of their lifecycles on the sea bottom. To discover the genomic information related to this unique behavior, we sequenced and compared the draft genomes of the upside-down jellyfish Cassiopea andromeda and Mastigias papua, Rhopilema esculentum from the same class of Scyphozoa alongside orthologs of other cnidarians. Genetic analysis revealed the diversity and phylogeny of cnidarian essential regulators Hox, POU domain genes associating with jellyfish sense and nerve. This study supported the hypothesis that there is no central Hox gene in cnidarians and found that there is a partial deletion of anterior Hox gene during the evolution of Scyphozoa and H. vulgaris. As for ParaHox in cnidarians, GSX and XLOX/CDX genes were all found in C. andromeda and R. esculentum, though M. papuapossessed only GSX gene. C. andromeda, R. esculentumandN. vectensis were found to have all 4 classes of POU genes while M. papua,A. aurita and H. vulgarishad only 2 POU gene classes, respectively. Among the cnidarians analyzed in this study, C. andromeda had the highest levels of nucleotide polymorphisms of the POU-1,-6 subtypes whileC. Andromeda, with higher diversity of POU-2/3/5 domain gene class, was closer to the corals and sea anemones than other scyphozoans. The parallels and differences of the adhesive-related proteins between three scyphozoans and H. vulgaris were summarized. C. andromedawas predicted to have unique adhesiverelated lectins (Rhamnose-binding lectin protein) and ferricchelate reductase which M. papua andR. esculentum did not. In summary, greater numbers of POU encoding genes and more complex POU isoforms maybe one of the key genetic factors that contribute to the upside down, “sleep like” state of C. andromeda. The result that adhesiverelated lectin proteins and reductase encoding genes remain in C. andromeda may be another potential genetic factor.