Includes bibliographical references / As there is limited information on the mechanisms of vegetative desiccation-tolerance in resurrection plant rhizomes, this work was undertaken to study the mechanisms of desiccation-tolerance in Mohria caffrorum rhizomes. Fronds of this plant have been previously characterized as being desiccation-tolerant in summer and desiccation-sensitive in winter. Since fern rhizomes are perennial organs, it was of interest to establish whether these organs are also perennially desiccation-tolerant and, whether or not the rhizomes regulate desiccation-tolerance in the fronds. Ultra-structural evidence using transmission electron microscopy and viability studies using electrolyte leakage analysis showed that the rhizomes were desiccation-tolerant throughout the seasons. Quantitative proteomics analysis using isobaric tags for relative and absolute quantification was employed to investigate molecular mechanisms of desiccation-tolerance in the rhizomes of this plant. Using a custom fern rhizome specific peptide sequence database, 236 proteins were identified. Of these, 16 proteins increased in abundance while 14 declined, in the summer collected rhizomes. On the other hand, 16 proteins increased in abundance and 20 declined in the winter form. Western blot analysis confirmed the expression trends of heat shock protein 70-2 and superoxide dismutase-[Cu-Zn], which were among the differentially expressed proteins. Bioinformatics analysis of the differentially expressed proteins was carried out using network enrichment tools, to identify key molecular processes and pathways involved in the rhizome response to desiccation stress. Results indicate that the rhizomes use different molecular mechanisms to achieve desiccation-tolerance in winter and summer. Potential cross-talks and cross-tolerances were identified in which mechanisms protecting the rhizomes against desiccation-tolerance appeared to also protect them against heat stress, and in winter an apparent cross-talk against desiccation and pathogen stresses was also identified. This study is the first report of evidence that M.caffrorum rhizomes are the 'master-regulator organs' responsible for regulating desiccation-tolerance in the fronds. This role was inferred from the rhizome's predicted up-/down-regulation of biological processes and pathways that relate to leaf senescence, shoot system morphogenesis and gametophyte development, among others.