A better understanding of the pathological mechanisms that drive neurodegeneration in people living with multiple sclerosis (MS) is needed to design effective therapies to treat and/or prevent disease progression. We propose that CNS-intrinsic inflammation and re-modelling of the sub-arachnoid space of the leptomeninges sets the stage for neurodegeneration from the earliest stages of MS. While neurodegenerative processes are clinically silent early in disease, ageing results in neurodegenerative changes that become clinically manifest as progressive disability. Here we review pathological correlates of MS disease progression, highlight emerging mouse models that mimic key progressive changes in MS, and provide new perspectives on therapeutic approaches to protect against MS-associated neurodegeneration.