There is a conceptual crisis in the biomedical sciences that is particularly salient in psychopathology research. Underlying the crisis is a controversy that pertains to the current medical model of disease that largely draws from causal-mechanistic explanations. The bedrock of this model is the analysis of biological part-dysfunctions that aims at unequivocally defining a pathological condition and demarcating it from its neighboring entities. This endeavor has led to a quest for physiological, biochemical, and genetic signatures. Yet, so far there is (...) little evidence for reliable biomarkers for any mental disorder. The contemporary biomedical paradigm largely ignores historical, dynamic, and system-level aspects—a view that has contributed much to the conceptual disjunction of the patient as a person from his/her disease. Notwithstanding the impressive progress in the biomedical sciences, increasingly more critics question whether the constituting framework is sufficient to convey a comprehensive understanding of illnesses, especially mental illnesses. Thus, the medical model urgently requires an update. But rather than revamping it by methodological advancements, it will be necessary to critically review its philosophical roots. The most problematic issues that require reworking are: the preponderance of the biostatistical theory; the undue decoupling of physiological from evolutionary explanations of function; the clinging to the Modern Synthesis ; and the neglect of dynamic and system-level properties. The proposed overhaul requires the heeding of historical explanations that draw from the Extended Evolutionary Synthesis as well as systems biology approaches for tackling multilevel and dynamic phenomena of complex systems. (shrink)