Prostate cancer (PC) is one of the leading causes of mortality amongst elderly men in the USA and is second only to lung cancer. African Americans (AA) are at an increased risk of developing PC and are more likely to die from the disease in comparison to Caucasian Americans (CA). Chromosomal alterations or genetic differences between AA and CA may account for the variances observed in PC progression. Importantly, mutations in the androgen receptor (AR) or the epidermal growth factor receptor (EGFR) may contribute to the disparity. Current studies are investigating the role of small nucleotide polymorphisms (SNPs) and microRNAs (miRNAs), which affect protein translation of the receptors by regulation of the 3' untranslated region (UTR), which may enhance the progression of PC. However, these genetic differences have not been fully explored in prostates between the two ethnic groups. This review will highlight the current studies on the EGFR signaling pathway as well as the involvement of SNPs and miRNAs and relate them to variances observed in PC of AA and CA men. With an understanding of these differences, specific preventive and therapeutic strategies may be developed to target personalized medicine for prostate carcinogenesis.