Axonal damage is believed to be the main factor contributing to disease progression in multiple sclerosis patients. The degeneration of axons could be the result of several different harmful events including inflammation and demyelination. Details of the mechanisms leading to axonal damage are, however, unknown, and distinct preclinical animal models can be used to study mechanisms operant during axonal injury development and progression. In this review article, we focus on the cuprizone model, a model for toxic, non-autoimmune-mediated demyelination. We discuss the relevance of this model to investigate demyelination and the pathophysiology of axonal degeneration. We further discuss the applicability of “cuprizone-combination” models to investigate the intricate interplay of innate and adaptive immune responses during demyelination and axonal degeneration.