In this paper I present an interpretation of du Bois-Reymond’s thesis on the impossibility of a scientific explanation of consciousness and of its present importance. I reconsider du Bois-Reymond’s speech “On the limits of natural science” (1872) in the context of nineteenth-century German philosophy and neurophysiology, pointing out connections and analogies with contemporary arguments on the “hard problem of consciousness.” Du Bois-Reymond’s position turns out to be grounded on an epistemological argument and characterized by a metaphysical skepticism, motivated by the unfruitful speculative tendency of contemporary German philosophy and natural science. In the final sections, I show how contemporary research can benefit from a reconsideration of this position and its context of emergence, which is a good vantage point to trace open problems in consciousness studies back to their historical development.