In multiple sclerosis (MS), there is significant evidence indicating that both progression independent of relapse activity (PIRA) and relapse-related worsening events contribute to the accumulation of progressive disability from the onset of the disease and throughout its course. Understanding the compartmentalized pathophysiology of MS would enhance comprehension of disease progression mechanisms, overcoming the traditional distinction in phenotypes. Smoldering MS activity is thought to be maintained by a continuous interaction between the parenchymal chronic processes of neuroinflammation and neurodegeneration and the intrathecal compartment. This review provides a comprehensive and up-to-date overview of the neuropathological and immunological evidence related to the mechanisms underlying PIRA phenomena in MS, with a focus on studies investigating the impact of currently available therapies on these complex mechanisms.