Literature suggests racial/ethnic minorities, particularly those who are less-acculturated, have stronger fatalistic attitudes toward cancer than do non-Latino Whites. Knowledge of cancer prevention is also lower among racial/ethnic minorities. Moreover, low knowledge about cancer risk factors is often associated with fatalistic beliefs. Our study examined fatalism and cancer knowledge by race/ethnicity and explored whether race/ethnicity moderate the association of fatalism with knowledge of cancer prevention and risk factors. We analyzed data from the Health Information National Trends Survey (2008), a national probability survey, to calculate population estimates of the associations among race/ethnicity, fatalistic beliefs, and knowledge about cancer from multivariable logistic regression. Racial/ethnic minorities had higher odds of holding fatalistic beliefs and lower odds of having knowledge of cancer risk factors than non-Hispanic Whites, and important differences by acculturation among Latinos were observed. Limited evidence of the moderating effect of race/ethnicity on the relationship between fatalistic beliefs and cancer risk factor knowledge was observed. Knowledge of cancer risk factors is low among all race/ethnicities, while fatalistic beliefs about cancer are higher among racial/ethnic minorities compared with non-Hispanic Whites. Implications for cancer education efforts are discussed.