A shared problem in psychology, psychiatry, and philosophy is how to define mental disorders. Various theories have been proposed, ranging from naturalism to social constructionism. In this article, I first briefly introduce the current landscape of such theories, before concentrating on one of the most influential approaches today: The harmful dysfunction theory developed by Jerome Wakefield. It claims that mental disorders are hybrid phenomena since they have a natural basis in dysfunctional mental mechanisms, but also a cultural component in the harm experienced by human beings. Although the theory is well thought through, I will raise a critical question: Is it possible to isolate mental mechanisms as naturally evolved from cultural factors? I will argue that it is not, but that the theory could still be helpful in an understanding of mental disorders, albeit on a new footing that does not operate with a natural and a cultural component as two separate factors. I argue that we need to develop a “naturecultural” approach to psychopathology that avoids mentalism, based on the fact that human beings are irreducibly persons.