Stress-related disorders (SRD) disproportionately affect women. Cortisol blunting, a failure to demonstrate a typical rise and fall of cortisol in response to stress, is associated with SRDs and has been found to be more pronounced among women. Cortisol blunting relates to both sex as a biological variable (SABV; e.g., estrogens and their fluctuations, impact on neural circuits) and gender as a psychosocial variable (GAPSV; e.g., discrimination, harassment, gender roles). I suggest a theoretical model linking experience, sex- and gender-related factors, and neuroendocrine substrates of SRD to the heightened risk among women. The model thus bridges multiple gaps in the literature to create a synergistic conceptual framework with which to understand the stress of being a woman. Utilizing such a framework in research may allow identifying targeted, sex-and gender-dependent risk factors, informing psychological treatment, medical advice, educational and community programming, and policy.