For the past 500 years, the American continent has been the site of ongoing mixing of Europeans, Native Americans, Africans and Asians, resulting in a significant percentage of Americans carrying ancestry from outside their self-identified race. However, genome-wide association studies (GWAS) and polygenic risk score (PRS) calculations have been performed and optimized on individuals of European descent, with minor exceptions. As part of CAST (Center for Admixture Science and Technology), we are developing methods to perform GWAS and calculate PRS on diverse and admixed populations, using large diverse cohorts, such as the All of Us and Million Veteran Program.