Living beings sense and respond to the inner and outer environmental changes in various ways. During the doctoral study, we dissected the distinct cellular mechanisms of mammalian cells in reacting and adapting to stress, especially under mild fever-like hyperthermia. Applying such conditions, more exactly a mild (40 °C) prolonged (0–12 h) heat stress and a moderate one (42.5 °C, 1 h) as well, we investigated cellular growth, Hsp induction, development of stress tolerance, cellular energy, lipidperoxidation, lipidomics, raft stability geneexpression in Chinese Hamster Ovary (CHO) cells. Our results indicate that mild heat triggers a distinct, dose-dependent remodeling of the cellular lipidome followed by the expression of heat shock proteins only at higher heat dosages. A significant elevation in the relative concentration of saturated membrane lipid species and specific lysophosphatidylinositol and sphingolipid species suggests prompt membrane microdomain reorganization and an overall membrane rigidification in response to the fluidizing heat in a time-dependent manner. RNAseq experiments reveal that mild heat initiates endoplasmic reticulum stress-related signaling cascades resulting in lipid rearrangement and ultimately in an elevated resistance against membrane fluidization by benzyl alcohol. To protect cells against lethal, protein-denaturing high temperatures, the classical heat shock protein response was required. The different layers of stress response elicited by different heat dosages highlight the capability of cells to utilize multiple tools to gain resistance against or to survive lethal stress conditions.