The TGF-β signaling pathway with its associated transcription factors (SMADs) was studied in the red-eared slider (Trachemys scripta elegans; liver, heart, white skeletal muscle, red skeletal muscle, and kidney) as a model for anoxia tolerance and the African clawed frog (Xenopus laevis; liver and muscle) as a model for dehydration resistance. In addition, protein expression levels of precursor cytokines were measured, as well as known genes and proteins downstream of the SMAD signaling pathway, such as c-Myc, and AP-1 proteins. The data showed that selective control of different SMAD isoforms occurred in response to environmental stress, the mechanism being reversible protein phosphorylation. Cellular responses and signaling profiles were observed to be highly tissue-specific and stress-specific. SMADs were shown to play a role in the hypometabolic response of both animal models through the regulation of cell cycle arrest, angiogenic processes, and oxidative injury management strategies.