This chapter unites evolutionary mismatch theory as conceived in the paradigm of population genetics with recent approaches focusing on the unit of the organism. Within the Extended Evolutionary Synthesis (EES), the attempt is being made to reintegrate developmental aspects into evolutionary thought. The developing organism is understood as a unit that cannot be reduced to an assemblage of isolated traits and that reacts to environmental challenges with capacities for plastic adaptation as well as niche construction. These capacities can successfully dissolve evolutionary mismatch situations, but at the same time produce different ones. Contemporary philosophy of biology also acknowledges the interlacing relationship of organism and environment with the concept of the holobiont and extended health accounts. A unification of evolutionary and developmental mismatch theory can thus inspire a relational and historically informed understanding of disease phenomena which can yield further benefits for human medicine.