Painted wood is a multi-layer structure composed of materials which swell or shrink differently in response to the sorption and desorption of moisture. The allowable levels of strain of the gesso layer were determined experimentally by subjecting specimens imitating historic panel paintings to mechanical stretching, and monitoring the development of cracks. These strain values were translated into the magnitudes of cyclic RH fluctuations allowable for unrestrained panel paintings, which depend on cycle duration, panel thickness and the configuration of moisture exchange of a panel with the environment. Panel paintings do not respond significantly to diurnal or shorter fluctuations irrespective of the panel thickness. The panels respond more and more significantly when the duration of the fluctuations increases until the panel fully responds to each cycle. The approach for calculating the accumulated fatigue damage from real-world climatic variations, being combinations of climatic cycles of various durations and amplitudes, was demonstrated.