When faced with environmental adversities, physical injury or senescence, medusae of Turritopsis dohrnii (Cnidaria, Hydrozoa) metamorphose back into the polyp stage preceded by an intermediate stage, the cyst. During its life cycle reversal, cell transdifferentiation, a mechanism in which a fully specialized cell switch into another needed cell type, occurs. To gather insight on the underlying genetic network of cell transdifferentiation and reverse development, we performed time-series and pair-wise differential gene expression analyses of the life cycle stages involved in the ontogenetic reversal of T. dohrnii. The time-series analyses identified genes that were enriched in the cyst during the reversal related to aging/lifespan, transposable elements, DNA repair/damage response and Ubiquitin-related processes, among others. The pairwise analyses revealed that in comparison to the colonial polyp, the medusa over-expresses genes involved in membrane transport, nervous system, mesoglea and muscle development and contraction, while genes involved in chitin metabolism, digestion, formation of the primary germ layer and cell specification processes are suppressed. Polyps formed from different developmental trajectories (asexual budding vs. reverse development) exhibited significant differences in transcriptional profile, with the reversed polyp being enriched with genes involved in processes such as chromatin remodeling/organization, matrix metalloproteinases and embryonic development, while suppressing genes involved in RAC G-protein signaling pathways. The presented genomic tools and data will further the potential of T. dohrnii as a research system to examine the genetic mechanisms and molecular drivers by which cells spontaneously leave a differentiated state to become a new lineage.