Epidemiological studies point to race as a determining factor in cancer susceptibility. In US registries recording cancer incidence and survival by race (distinguishing 'black versus white'), individuals of African ancestry have a globally increased risk of malignancies compared with Caucasians and Asian Americans. Differences in socioeconomic status and health-care access play a key role. However, the lesser disease susceptibility of Hispanic populations with comparable lifestyles and socioeconomic status as African Americans (Hispanic paradox) points to the concomitant importance of genetic determinants. Here, we overview the molecular basis of racial disparity in cancer susceptibility ranging from genetic polymorphisms and cancer-driver gene mutations to obesity, chronic inflammation, and immune responses. We discuss implications for race-adapted cancer screening programs and clinical trials to reduce disparities in cancer burden.