Abstract Colorectal cancer is the third most common cancer and the third leading cause of cancer deaths in the US and the incidence of colorectal cancer in African Americans is higher than the general population. Furthermore, survival among African American patients with colorectal cancer remains significantly lower than other racial groups. Therefore, colorectal cancer in African American patients still remains a debilitating disease and there is an unmet need to further understand the biology and specifically tumor heterogeneity of this disease to develop new therapeutic approaches for these patients in order to improve treatment and overall prognosis. In our preliminary work, we have developed a droplet-based microfluidics based technology to generate miniature droplet organoids (MDO) that can be used to grow single cancer cells to study tumor heterogeneity and drug resistance. Thus, our overall hypothesis is that MDO is the only method that can be used to systematically study tumor heterogeneity both functionally and genomically. We now propose to test our hypothesis by 1) Generating miniature droplet organoids (MDO) from patients of African ancestry with CRC in order to perform high-throughput drug screens to study tumor heterogeneity and 2) Systematically characterize the epigenomes of the clonal CRC MDO populations and associate them with tumor growth heterogeneity and resistance to therapy. In summary, these studies will take important steps toward understanding tumor heterogeneity in order to develop and validate new and potent therapies in African American colorectal cancer patients that can be successfully translated into the clinic.