Ctenophores’ amazing capacity of regeneration has fascinated biologists for centuries. The morphological features of ctenophore regeneration have been documented, but the molecular and cellular components behind this phenomenon have remained a mystery. Here, next generation sequencing technologies and transcriptomic analysis are used to investigate the regeneration dynamics in the ctenophore Mnemiopsis leidyi. The resulting data identify multiple signaling pathways that might be involved in ctenophore regeneration. These include evolutionarily conserved pathways, such as Ca2+-dependent and MAP-kinase signaling pathways, that are up regulated during regeneration, as well as genes involved in energetics and cytoskeleton function. The data also show evidence for involvement of dozens of ctenophore specific secretory molecules, their receptors and processing components that are important signal messengers in regeneration. A unique subset of transcription factors were also found to be involved in regeneration which may be upstream regulators of those signaling pathways. In summary, our data indicate that the strategies which ctenophores employ to regenerate use a unique combination of evolutionarily conserved and ctenophore specific signaling components. These data provide novel insights into the mechanisms of regeneration in the earliest branching taxa in Metazoa. Overall design: Transciptomic evalutation of control tissue vs regenerating tissue at 30 minutes, 1 hour and 2 hours after regeneration. This tested both in total RNA and nascent RNA.