Dendrobium wangliangii is an endangered and epiphytic orchid with tolerance to seasonally extreme arid conditions and occurs exclusively in the hot-dry valley area of southwestern China. To reveal its molecular basis responsible for ecological adaptation, large-scale transcriptome sequencing was performed using Illumina sequencing with pooled mRNA extracted from whole plants and pseudobulbs during drought and rainy seasons. Based on the target transcript selection, the differentially expressed genes were related to 8 well-known drought-tolerant categories, and to morphological traits in resistance to water stress including pseudobulbs and roots. Further gene ontology enrichment analysis revealed that ‘nucleoside/nucleotide and ribonucleoside/ribonucleotide metabolic processes' and ‘response to stimulus' were the two most important aspects in resistance to drought stress with respect to the whole plant. In addition, the difference in the number and category of differentially expressed genes in whole plant and stem suggested the involvement of genes specifically localized in the stem, such as GTP-binding protein, lipases, signaling related transcripts and those involved in the ATP metabolic process. The comprehensive analysis of the epiphytic orchid in response to water deprivation indicates that integral tactics lead to active adaptation as a basal defense response to drought stress by the endangered epiphyte, including the collaboration of metabolic processes, responses to a various stimulus and other candidate genes contribute to its extreme drought tolerance. Insights from this study can be further utilized to understand stress-responsive genes in other medicinally important species and to improve the drought tolerance of food crops.