Purpose of Review <p>Researchers and clinicians have increasingly recognized the importance of investigating and considering sex differences in obesity treatment. In this narrative review, we first summarized sex differences in select obesity-related conditions that have been the focus of studies of second-generation anti-obesity medications (i.e., semaglutide and tirzepatide) including type 2 diabetes, obstructive sleep apnea, knee osteoarthritis, and heart failure. We next described sex differences related to obesity treatments with a focus on the second-generation anti-obesity medications, semaglutide and tirzepatide.</p> Recent Findings <p>Type 2 diabetes, obstructive sleep apnea, knee osteoarthritis, and heart failure demonstrated sex-specific pathways influenced by factors such as hormones and body composition. Lifestyle modification, on average, resulted in larger weight losses in males. In contrast, second-generation AOMs produced higher mean weight losses among females. Females reported more adverse events (e.g., nausea, vomiting) with second-generation anti-obesity medications. The few studies that have performed analyses of changes in obesity-related comorbidities stratified by sex have shown consistent improvements between males and females in heart failure and cardiovascular outcomes.</p> Summary <p>Studies are needed to evaluate the effect of sex on the efficacy of anti-obesity medications including on mental health, investigate the mechanisms underlying these effects, and develop interventions to improve the availability and access of these medications.</p>