This article discusses and reviews advanced forms of serial morphometry in the context of a disease progression model in multiple sclerosis (MS). This model of disease activity distinguishes between overall disease activity and the proportion thereof that becomes permanent damage. This translates into a progression model that features a repair potential, which, when exhausted, marks the conversion or progression from relapsing to progressive disease. The level of repair capacity at a given time determines the rate of progression. Both clinical and MRI variables appear to be in support of such a model. We examine possible MRI markers for this repair capacity, particularly the short-term behavior of new MRI lesions, quantified by methods of time-series analysis—that is, capturing lesion dynamics in the form of MRI intensity change directly, rather than shape or volume change. Lower rates of individual lesion recovery may represent lower repair and greater proximity to a progressive stage. Individuals with low transient lesion turnover appear to undergo more rapid progression and atrophy. Because disease-modifying therapies aim to alter the pathophysiological chain of inflammation, demyelination, and axonal loss, a therapeutic effect may therefore be more readily apparent as a change in lesion dynamics and recovery rate and level, rather than a change in total lesion burden or enhancing lesion number.