Hymenoglossum cruentum (Hymenophyllaceae) is a poikilohydric, homoiochlorophyllous desiccation-tolerant (DT) epiphyte fern. It can undergo fast and frequent dehydration-rehydration cycles. This fern is highly abundant at high-humidity/low-light microenvironments within the canopy, although rapid changes in humidity and light intensity are frequent. The objective of this research is to identify genes associated to desiccation-rehydration cycle in the transcriptome of H. cruentum to better understand the genetic dynamics behind its desiccation tolerance mechanism. H. cruentum plants were subjected to a 7 days long desiccation-rehydration process and then used to identify key expressed genes associated to its capacity to dehydrate and rehydrate. The relative water content (RWC) and maximum quantum efficiency ( F v/ F m) of H. cruentum fronds decayed to 6% and 0.04, respectively, at the end of the desiccation stage. After re-watering, the fern showed a rapid recovery of RWC and F v/ F m (ca. 73% and 0.8, respectively). Based on clustering and network analysis, our results reveal key genes, such as UBA/TS-N, DYNLL, and LHC, orchestrating intracellular motility and photosynthetic metabolism; strong balance between avoiding cell death and defense ( CAT3, AP2/ERF) when dehydrated, and detoxifying pathways and stabilization of photosystems ( GST, CAB2, and ELIP9) during rehydration. Here we provide novel insights into the genetic dynamics behind the desiccation tolerance mechanism of H. cruentum.