This review highlights molecular genetic studies of monogenic traits where common pathogenic mutations occur in black families from sub-Saharan Africa. Examples of founder mutations have been identified for oculocutaneous albinism, cystic fibrosis, Fanconi anemia, and Gaucher disease. Although there are few studies from Africa, some of the mutations traverse populations across the continent, and they are almost all different from the common mutations observed in non-African populations. Myotonic dystrophy is curiously absent among Africans, and nonsyndromic deafness does not arise from mutations in GJB2 and GJB7. Locus heterogeneity is present for Huntington disease, with two common triplet expansion loci in Africa, HTT and JPH3. These findings have important clinical consequences for diagnosis, treatment, and genetic counseling in affected families. We currently have just a glimpse of the molecular etiology of monogenic diseases in sub-Saharan Africa, a proverbial “ears of the hippo” situation.