This chapter deals with the evolution of scientific epistemology following the impact of Kant’s critical philosophy, which emphasized the role of epistemology in learning and decision-making and sought to synthesize Empiricism and Rationalism. Kant’s ‘Copernican revolution’ shifted the focus of research towards the epistemic subject. This shift redefined the need for exploring the limits of knowledge and establishing the conditions for reliable scientific inquiry, while acknowledging the structuring role of the mind. Post-Kantian developments diverged in different cultural environments. German Idealism, notably Hegel, employed teleological dialectics to resolve the Kantian antinomies, viewing science as driven progressively towards a metaphysical ‘absolute’. The diverging paradigm of positivism, championed by Comte, emphasized the crucial role of empirical evidence in science. This paradigm focused on the capacity of prediction within the frame of a teleological view of progress. The nineteenth century saw also the rise of evolutionary thinking, first in biology (Darwin) and physics (thermodynamics). Mach aimed to integrate Darwinism and experimental psychology, influencing the genesis of the Vienna Circle. This circle fostered logical positivism, merging empiricism with formal logic, using the verifiability principle as a demarcation criterion between science and metaphysics. Internal tensions and intrinsic limitations led to its post-war decline paving the way for the emergence of post-positivism.