Colorectal cancer (CRC) is a leading cause of cancer morbidity and mortality. Effective prevention and early detection may be achieved through screening, but screening rates are low, especially in American Indian (AI) populations. We wanted to understand perceptions of CRC screening among AI located in the Great Lakes region. Focus groups were recorded and transcribed verbatim (N = 45). Data were analyzed using qualitative text analysis. Themes that deterred CRC screening were low CRC knowledge, fear of the procedure and results, cost and transportation issues, and a lack of quality and competent care. Suggestions for improvement included outreach efforts and culturally-tailored teaching materials.