Although cancer clinical trials are important for discovering lifesaving therapies, participation remains low among racial/ethnic minorities, and little research explores the role of health literacy in racial/ethnic minority perceptions of cancer clinical trials (CCTs). Five focus groups (n = 50) with African American and Hispanic participants explored CCT perceptions using a multidimensional health literacy framework. We found poor scientific literacy including misconceptions of scientific information, perceptions of clinical trials as uncertain and fear; limited civic literacy around topics of trust, perceptions of participants as guinea pigs, and concerns about of IRB protections; and cultural literacy challenges regarding the importance of home remedies for health, use of native language, and the importance of race/ethnicity matching to health care professionals. Results highlight the importance of attending to scientific literacy, cultural literacy, and civic literacy. Future educational interventions regarding cancer clinical trials should address the importance of health literacy in understanding cancer clinical trial decision making.