Past clinical trials addressing behavior modification for cardiovascular disease (CVD) prevention have not been culturally appropriate for African Americans. This supposition is borne out by the continued challenges researchers face not only in recruiting and retaining African Americans in clinical trials, but also in achieving the desired outcomes among this population. Investigators have limited resources to develop culturally appropriate CVD prevention trials. The scientific literature reveals 2 models for implementing culturally appropriate interventions applicable to CVD prevention among African Americans; however, these models are not easily applied to the clinical trial setting. We propose a new model for developing a culturally appropriate clinical trial. The clinical trial is a function of the investigator's cultural framework, meaning that an investigator will have more difficulty designing clinical trials appropriate for use with cultures other than his or her own, a definite limitation when attempting to effectively reach diverse populations. Differences between the cultural frameworks of most clinical trials and African Americans' cultural frameworks lead to intrinsic biases, limiting the ability of African Americans to achieve the desired outcomes for any particular trial. An African-American participant's degree of immersion in traditional African-American culture, or acculturation, influences the magnitude of these biases. Investigators must be aware of, and attempt to mitigate, such biases so that the trial's potential for success is equitable across ethnic groups. In addition, investigators must understand how to effectively address relevant biases of African Americans without challenging their ethnic identity. Steps to decrease biases are described.