Sex differences are evident in nearly all complex traits. Various diseases, including but not limited to, autoimmune, neurological, and psychiatric disorders, display sex differences in prevalence, onset, progression, or severity. Furthermore, given that several drugs are metabolized differently between the sexes, there are sex differences in response to various treatments. To improve treatment for such diseases and adverse drug response, it is crucial to uncover the molecular basis for the sex differences and their consequences on organ and systemic function. Sexually differentiated traits and phenotypes stem from a combination of factors, including genetics (gene variants-by-sex interactions, XY chromosome complements, genomic imprinting), the hormonal milieu, and gene regulation. The four core genotypes (FCG) mouse model, created in the 1990’s, has allowed for extensive investigation of sex differences in disease and the underlying biological factors, namely sex chromosome complement and sex hormones. The FCG model creates XX gonadal males, XX gonadal females, XY gonadal males, and XY gonadal females. To date, the FCG mouse model has been used to uncover sex chromosome and hormone contributions to sex differences in a wide variety of phenotypes, including brain and behavior, immunity and autoimmunity, metabolism, and Alzheimer’s disease. However, the mouse FCG model has significant limitations, as mice and humans are not genetically identical, thus, many biological mechanisms differ between the two species. Rats have many advantages as a model species over mice, given their enhanced recapitulation of human conditions, such as cardiovascular and behavioral conditions. In collaboration with researchers from around the world, we have created a rat FCG model which can be used to investigate underlying mechanisms to sex differences in various phenotypes, drug responses, and diseases. We aimed to elucidate the biological factors (XY chromosome complements and/or gonadal hormones) underlying the sex-biased genes and pathways involved in sex-biased conditions. We have performed RNA-sequencing of the FCG rats on various tissues implicated in sex-biased diseases. We identified genes that display sex chromosomal- and gonadal hormone- dependent expression. Next, we overlapped our transcriptomic findings with genes and pathways that display sex differences in sex-biased human conditions, including Parkinson’s disease, autism, and schizophrenia. In the future, the rat FCG model can be crossed with disease models, and may then be utilized to elucidate the basis of a sex bias in the disease of interest. We anticipate that future application of the unique rat FCG model will significantly enhance the understanding of sex as a biological variable in medical research and practice.