Methods, systems, and apparatus, including medium-encoded computer program products, for computer aided design of physical structures using generative design processes. A method includes obtaining a design space for a modeled object, one or more design criteria, one or more in-use load cases, and one or more specifications of material, wherein the design criteria comprise a required number of loading cycles for the modeled object; iteratively modifying a generatively designed three dimensional shape of the modeled object, comprising: performing numerical simulation of the modeled object, finding a maximized stress or strain element for each of the one or more in-use load cases, determining an expected number of loading cycles for each of the one or more in-use load cases, redefining a fatigue safety factor inequality constraint for the modeled object, computing shape change velocities in accordance with at least the fatigue safety factor inequality constraint, and updating the level-set representation.