Panel paintings are multi-layer structures composed of humidity-sensitive materials. Preventing or limiting stresses in these structures, generated by the loss or gain of moisture, requires an understanding of the relevant processes and risks. A three-dimensional elastic model of a panel painting was used to analyse surface stresses and understand how hierarchical crack patterns are formed in the two-layer structure of the pictorial layer – the gesso and the paints. Two historically important paint types were considered ‒ egg tempera and oil paints, laid on a gesso produced following historical procedures. Two scenarios of stress development were analysed: cumulative drying shrinkage of paints or gesso, owing to gradual loss of water or evolution of the molecular composition of the binders, and moisture-induced swelling of the wood substrate. Ratios of distances between cracks in the tangential and longitudinal directions of a wood panel to the layer thickness were estimated for increasing magnitudes of materials’ dimensional response in the two scenarios. The critical values of the ratios for which stress in the midpoint between the cracks dropped below the value inducing strain at break in the materials and saturation of the crack patterns occurred, was approximately 3–4 or 5–6 for the paints and the gesso, respectively. The critical distance normalized to the gesso thickness between cracks parallel to the wood grain induced by swelling of the wood substrate due to relative humidity variation in the range of 50–70% was 6. The study demonstrated that crack spacings in the fully developed crack systems remain sensitive only to the thicknesses of paint or gesso layers which, therefore, can be derived from the crack pattern geometry. Existing flaws in gesso were found not to increase the risk of new crack development.