Natural selection, drift, and gene flow are the three major evolutionary forces at the origin of genetic diversity among human populations. To further explore these mechanisms, we present an innovative approach using various medical genetic markers and focusing on the Basque population. From this study we can confirm the important role of drift in this endogamous human group and can report some disorders related to founder effects. Most important, the peculiar distribution of various polymorphisms, such as blood group O, factor V Leiden, DF508, C282Y, and CCR5 D32 mutations, which are implicated in resistance to infection, hemostasis, or iron conservation, could be interpreted as an adaptive profile. Multidisciplinary data have shown that the Neolithic period arrived significantly later in this southwestern corner of Europe. We hypothesize that the long-lasting Paleolithic mode of life, especially regarding nutrition and microbial exposure, was at the origin of this selective pressure within this population of ancient local ancestry. This approach could open new avenues in the field of population genetics.