This study explored the direct and moderational effects of a number of psychosocial factors on the perceived stress of African-American college students. One-hundred and forty six African-American college students completed measures of perceived stress, optimism, hostility, social support, religiosity, self-esteem, cultural mistrust, perceived racism, and coping strategies. Optimism and self-esteem were negatively correlated with perceived stress while extrinsic religiosity, perceived racism in academic settings, cultural mistrust, and hostility were positively correlated with perceived stress. In turn, perceived stress was negatively correlated with four approach-oriented and six avoidant-oriented coping strategies. Acceptance coping moderated the relationship between hostility and perceived stress while optimism and the planning coping moderated the relationship between perceived racism in academic settings and perceived stress. These findings suggest that cognitive-behavioral prevention programs that seek to alleviate stress among African Americans should incorporate skill building activities that are culturally sensitive, emphasize the importance of optimism and high self-esteem, encourage active coping and planning, and discourage denial, behavioral disengagement, and mental disengagement.