<p>Multiple sclerosis is a chronic neuro-inflammatory and neurodegenerative disease, traditionally characterized by the presence of focal demyelinating lesions in the CNS. However, accumulating evidence suggests that multiple sclerosis pathophysiology extends beyond such classical lesions, affecting also ‘normal’ appearing tissue in both white and gray matter, referred to as ‘normal-appearing white matter’ and ‘normal-appearing gray matter’, respectively. Here, we provide a comprehensive overview of the widespread biochemical, cellular, and microstructural alterations occurring in these ‘normal-appearing’ CNS regions. Additionally, we discuss the evidence derived from human post-mortem studies that support that normal-appearing white and gray matter could be the drivers of smoldering-associated pathological worsening once repair mechanisms are exhausted. Comprehensive understanding of multiple sclerosis pathology beyond classical lesions not only provides a more complete picture of disease progression, but also provides further insights into potential novel therapeutic avenues in order to slow or halt disability accumulation.</p>