There is tremendous sexual dimorphism in human genetic disease susceptibility, progression, and drug response. It is thus alarming that most genome-wide association studies exclude the most sexually dimorphic regions of our genome, the sex chromosomes. An essential component of incorporating the X and Y into studies of human disease, with their unique inheritance patterns, and response to population history and selection, is to understand their evolutionary history. Ancestrally, both the X and Y chromosomes shared identical gene content, but throughout our evolutionary history the Y chromosome has lost over 90% of the gene content it once shared with the X. The loss of Y-linked sequence not only affects the fate of the Y chromosome, but it also modulates the evolution and expression of X-linked genes. XX humans inactivate gene expression on one of their X chromosomes, but not completely; 15% of genes escape X-inactivation, while another 10% escape X-inactivation in only a subset of individuals. Analyzing patterns of heterogeneous X-inactivation across individual cell lines, we show that genes on the X chromosome are silenced in response to gene loss on the Y. Variation in these patterns of silencing are important for understanding the etiology of, and variation in, X-linked diseases. Learning Objectives: 1. Explain the importance of including the human X and Y chromosomes in clinical and genetic analysis. 2. Appreciate the role of the sex chromosomes in human health and disease 3. Discuss the implications of human Y chromosome variation.