Many providers face challenges when making decisions regarding laboratory test results that fall outside the normal range. Slight deviations from the reference range can occasionally result in additional lab tests, unnecessary referrals, and unjustified investigations. African Americans, for genetic and other reasons, frequently present with results that are “slightly off.” These deviations from Euro-centric reference ranges are well recognized but often overlooked by busy clinicians. This chapter reviews the nuanced differences in blood laboratory results and trends that exist among African American patients, including variations in CBC, metabolic panel, lipid panel, and cancer markers. Laboratory reference interval differences by race (and gender) have been acknowledged for many years, yet clinical laboratories have been slow to adopt race- or gender-linked reference ranges. The chapter also includes an overview of common hematological disorders in African Americans, featuring a detailed examination of sickle cell anemia, along with thalassemia and glucose-6-phosphate dehydrogenase (G6PD) deficiency. These so-called disorders were, in fact, life-saving genetic adaptations to environmental dangers and not diseases at all.