Tacrolimus is dependent on CYP3A5 enzyme for metabolism. Expression of the CYP3A5 enzyme is controlled by several alleles including CYP3A5∗1, CYP3A5∗3, CYP3A5∗6 and CYP3A5∗7. African Americans (AAs) have on average higher tacrolimus dose requirements than Caucasians; however, some have requirements similar to Caucasians. Studies in AAs have primarily evaluated the CYP3A5∗3 variant; however, there are other common nonfunctional variants in AAs (CYP3A5∗6 and CYP3A5∗7) that do not occur in Caucasians. These variants are associated with lower dose requirements and may explain why some AAs are metabolically similar to Caucasians. We created a tacrolimus clearance model in 354 AAs using a development and validation cohort. Time after transplant, steroid and antiviral use, age and CYP3A5∗1, ∗3, ∗6 and ∗7 alleles were significant toward clearance. This study is the first to develop an AA-specific genotype-guided tacrolimus dosing model to personalize therapy.