The African clawed frog, Xenopus laevis, has been used as a model organism for cellular and developmental biology for nearly a century. Comparatively unstudied is its natural tolerance to dehydration brought about by seasonal drought evaporating its aquatic habitats. To survive the loss of >30% body water content, these animals employ several tissue-specific adaptations ranging from switching to ureotelism to relying on anaerobic metabolism as oxygen transport decreases with increased blood viscosity. Previous studies have indicated dehydration responsive gene expression and function is regulated with multiple mechanisms. In this thesis I further establish X. laevis as a dehydration tolerance model organism by determining suitable RT-qPCR reference genes in eight tissues. I then investigate regulatory mechanisms capable of large-scale regulation, namely, DNA methylation and histone modifications, microRNA, and reversible protein phosphorylation. Global levels of epigenetic marks showed little response to dehydration apart from increased 5hmC and decreased H3K4me in the liver, suggestive of epigenetic reprogramming. MicroRNAs, which are short RNAs that negatively regulate translation of specific mRNAs, were then examined in the heart. This analysis revealed a trend of downregulation during dehydration, and the enrichment of several important pathways including cardiac muscle contraction and glycolysis and gluconeogenesis. Particularly telling is the near uniform prediction of decreased regulation of all glycolytic enzyme transcripts that may support increased anaerobic glycolysis capacity during dehydration. Next, I analyzed the liver and skeletal muscle phosphoproteomes during dehydration and found a strong and concerted response by the liver and not muscle. Also emerging from the data was the significant upregulation and phosphorylation of a hypoxia inducible PFKFB isozyme in the liver known to support glycolysis in many cancers. Together these results significantly advance our understanding of the molecular biology of dehydration tolerance and provide multiple clear directions for future studies.