Abstract Although cardiovascular disease (CVD) has traditionally been regarded as a higher risk condition in men, it is also the leading cause of death in women. The impact of sex and gender on the pathophysiology of CVD has emerged as an important clinical issue but its molecular mechanisms are poorly understood. The intersection of sex, gender and CVD is underscored by recent observations that transgender individuals undergoing gender affirming sex hormone therapy (GHT) are at increased CVD risk. Sex-differentiation of insulin resistance, a major CVD risk factor, may underlie these observations since insulin resistance arises from adipose, a sexually dimorphic tissue that is highly susceptible to sex hormones. Unfortunately, options to treat insulin resistance- mediated CVD risk in a sex- and gender-relevant fashion are limited particularly in women. For example, thiazolidinediones (TZDs), the only pharmacologic class that specifically targets insulin resistance in adipose, increase the risk of osteoporotic fractures in post-menopausal women. A molecular understanding of the roles of chromosomal sex, sex hormones and gender on the development of insulin resistance is needed to enhance screening and develop new therapeutic options for CVD in women and transgender individuals. One approach to identifying the molecular determinants of insulin resistance specifically operational in women is to conduct genetic association studies (GWAS) of insulin resistance stratified by sex. However, isolating the relative impacts of chromosomal sex, sex hormones, and gender and establishing a mechanistic relationship between phenotype and identified genetic variants remains a major challenge. Here, we propose to: 1) Utilize an integrative genomic approach by leveraging the natural “crossover” experiment between sex chromosomes, hormones and gender that occurs in transwomen and men undergoing GHT; and 2) Directly test the impact of perturbing putatively causal genes on CVD risk in women by using high throughput assays for insulin resistance to functionally characterize protein-coding genetic variants identified in 273,000 women. This work will systematically identify sex- and gender-specific insulin resistance genes and for several top- ranked genes, assess the clinical effect on CVD in women by relating genetic variants to function to phenotype.