A framework based on the condition-dependent development and expression of sexually selected traits is used to generate a priori predictions of human sex-specific cognitive vulnerabilities. At its foundation is the efficiency of mitochondrial energy capture and control of oxidative stress and the key idea is that more elaborated traits are more vulnerable to stressors because they require more energy to build, maintain, and express. Sexually selected traits support competition for reproductive resources and influence mate choices and are generally more elaborated than other traits. They are fully developed and expressed under favorable conditions, but under less favorable conditions they are more severely compromised than are other traits. The framework is used to identify traits that are theoretically more vulnerable in girls and women, and other traits that are theoretically more vulnerable in boys and men. The utility of this approach is evaluated in terms of sex-specific cognitive deficits associated with malnutrition, infectious disease, diabetes and insulin resistance, Alzheimer’s disease and other dementias, and exposure to industrial compounds, intoxicants, and chemotherapy. This evolutionary approach helps to organize what is known about cognitive deficits associated with stressor exposure and provides clear implications for future research and risk assessment.