Heat shock (HS), like many other stresses, induces specific and highly regulated signaling cascades that promote cellular homeostasis. The three major mitogen-activated protein kinases (MAPK) and protein kinase B (PKB/Akt) are the most notable of these HS-stimulated pathways. Their activation occurs rapidly and sooner than the transcriptional upregulation of heat shock proteins (Hsp), which generate a transient state of extreme resistance against subsequent thermal stress. The direct connection of these signaling pathways to cellular death or survival mechanisms suggests that they contribute importantly to the HS response. Some of them may counteract early noxious effects of heat, while others may bolster key apoptosis events. The triggering events responsible for activating these pathways are unclear. Protein denaturation, specific and nonspecific receptor activation, membrane alteration and chromatin structure perturbation are potential initiating factors.