Methods, systems, and apparatus, including medium-encoded computer program products, for computer aided design of physical structures using generative design processes. A method includes performing numerical simulation of a modeled object in accordance with a current version of the three dimensional shape and the one or more in-use load cases; finding a maximized stress or strain element, for each in-use load cases; determining an expected number of loading cycles for each of the one or more in-use load cases for the physical structure using the maximized stress or strain element and data relating fatigue strength to loading cycles; redefining a fatigue safety factor inequality constraint for the modeled object; computing shape change velocities for an implicit surface in a level-set representation of the three dimensional shape in accordance with at least the fatigue safety factor inequality constraint; and updating the level-set representation using the shape change velocities.