After having encountered evolutionary mismatch theory as an explanation for extinction risks, this chapter is concerned with the theory as an explanation for human vulnerabilities to disease. During this discussion, the obstacles that mismatch theory as presented by N&W faces in the attempt to fulfill this explanatory task become apparent. In the first part of this chapter, I show which disease type mismatch theory is designed to explain (5.1.1), what kind of entity is affected (5.1.2) and how evolutionary mismatches are related to human vulnerability (5.1.3). Afterwards I proceed to present the transition of mismatch theory from an ecological to a medical context which involves explanatory challenges. In the previous chapter we have learned how mismatch theory is successfully applied as an explanation for extinction risks in ecology. In evolutionary medicine though, its explanatory potential is less obvious. To show why, I chronicle the historic development of mismatch arguments in medicine (5.2) and then proceed to discuss the argumentative structure (5.3) including the three cornerstones that constitute a mismatch argument in the context of human medicine: The environment of evolutionary adaptedness (5.4.1), novelty (5.4.2) and adaptive capacity (5.4.3). The concluding part (5.5) poses the question whether mismatch theory is itself mismatched to fulfill the explanatory tasks set up for it in the context of evolutionary medicine.