Sporadic findings in humans suggest that re-induction of heat acclimation (AC) after its loss occurs markedly faster than that during the initial AC session. Animal studies substantiated that the underlying acclimatory processes are molecular. Here we test the hypothesis that faster re-induction of AC (ReAC) implicates ‘molecular memory’. In vivo measurements of colonic temperature profiles during heat-stress and ex vivo assessment of cross-tolerance to ischemia/reperfusion or anoxia insults in the heart, demonstrated that ReAC only needs 2 days vs the 30d required for the initial development of AC. Stress gene profiling in the experimental groups highlighted clusters of transcriptionally activated genes (37%), which included heat shock protein (HSP) genes, anti-apoptotic genes, and chromatin remodeling genes. Despite a return of the physiological phenotype to its pre-acclimation state, after a one-month de-acclimation (DeAC) period, the gene transcripts did not resume their pre-acclimation levels, suggesting a dichotomy between genotype and phenotype in this system. Individual detection of hsp70 and hsf1 transcripts agreed with these findings. HSP72, HSF1/P-HSF1 and BCLxl protein profiles followed the observed dichotomized genomic response. In contrast, HSP90, an essential cytoprotective component mismatched transcriptional activation upon DeAC. The uniform activation of the similarly responding gene clusters upon De/Re-AC implies that re-acclimatory phenotypic plasticity is associated with upstream denominators. During AC, DeAC, and ReAC, the maintenance of elevated/phosphorylated HSF1 protein levels and transcriptionally active chromatin remodeling genes implies that chromatin remodeling plays a pivotal role in the transcriptome profile and in preconditioning to rapid cytoprotective acclimatory-memory.