Halobacterium salinarum is an extremely halophilic archaeon that inhabits high-salinity aqueous environments in which the temperature can range widely, both daily and seasonally. An OMICS analysis of the 37°C and 49°C proteomes and transcriptomes for revealing the biomodules affected by temperature is reported here. Analysis of those genes/proteins displaying dramatic changes provided a clue to the coordinated changes in the expression of genes within five arCOG biological clusters. When proteins that exhibited minor changes in their spectral counts and insignificant p values were also examined, the apparent influence of the elevated temperatures on conserved chaperones, metabolism, translation, and other biomodules became more obvious. For instance, increases in all eight conserved chaperones and three arginine deiminase pathway enzymes and reductions in most tricarboxylic acid (TCA) cycle enzymes and ribosomal proteins suggest that complex system responses occurred as the temperature changed. When the requirement for the four proteins that showed the greatest induction at 49°C was analyzed, only CctA (chaperonin subunit α), but not Hsp5, DpsA, or VNG1187G, was essential for thermotolerance. Environmental stimuli and other perturbations may induce many minor gene expression changes. Simultaneous analysis of the genes exhibiting dramatic or minor changes in expression may facilitate the detection of systems level responses.