Rhinoviruses and enteroviruses are leading causes of human infections. Although closely related within the Enterovirus genus, they are characterized by an important variability, illustrated by the existence of over 250 types. This genetic diversity is paralleled by a phenotypic diversity. Rhinovirus infection is mostly restricted to the respiratory tract, whereas enteroviruses can cause viremia, spread to multiple sites and have been associated with 20 clinically recognized syndromes, including central nervous system complications. The genomic features underlying these distinct phenotypes have not been elucidated yet. We aim at addressing this gap by using a complementary approach involving basic molecular virology and applied research. Our studies include: the analysis of forces driving rhinovirus and enterovirus evolution, and the investigation of transmission, adaptation and acquisition of new phenotypic features during human infections. Our results give an overview on the mechanisms underlying the evolution of these versatile viruses, which helps better understand their pathogenesis.