Plasticity of the thermoregulatory system is a key factor for the induction of heat acclimation. Temperature-adaptive shifts in gene expression play an essential role in the processes involved. This review attempts to bridge the gap between the classical physiological heat acclimation profile and the molecular/cellular mechanisms underlying the evolution of the acclimated phenotype. Essential acclimatory modifications linked with thermal tolerance are (i) neuronal plasticity (ii) cytoprotection. Leftward and rightward threshold shifts in these respective functional categories expand the dynamic thermoregulatory range of the acclimated phenotype. Neural plasticity depends on changes in hypothalamic warm/cold sensitive neuron ratio and excitability. Over the course of acclimation, there is marked upregulation of transcripts encoding voltage dependent K+ and Ca2+ channels, neurotransmitters and/or their receptors. Temperature threshold for thermal injury is associated with progressive enhancement of inducible cytoprotective networks including the essential acclimatory components HSP70, HSF1 and HIF-1. Via cross-tolerance, achieved through shared on-call cytoprotective networks, acclimation also renders protection against novel stressors. Collectively, heat acclimation is a within life evolutionarily beneficial phenomenon with a memory, imprinted via epigenetic mechanisms.