Multiple sclerosis (MS) has entered an era of immunomodulatory drug treatment, the impact of which on long-term disease progression remains controversial. The increasing use of these therapies has intensified our need to understand the true natural history of MS. The MS community is poised to establish whether the immunomodulatory drugs exhibit long-term benefits, with a suitable untreated natural history cohort likely the most practical and ethical comparator group. Thus, a thorough understanding of the natural history of MS is fundamental. In this review, we highlight recent advances in MS natural history over the last 5 years, with a focus on long-term population-based cohorts and factors associated with disease progression. Survival in MS has increased and longer times to irreversible disability have been reported in contemporary studies, indicating a slower accumulation of disability. Wide variation in the MS disease trajectory is evident within and between natural history studies, reflecting both methodologic considerations related to data collection and heterogeneity of disease activity. Recent publications have indicated that a younger age at disease onset is no longer indicative of a favorable outcome and further evidence supports the dissociation between relapses and long-term disability, although windows of opportunity may exist for some patients. We are now perhaps faced with our last chance to examine the true natural history of MS, so whether the reader is a practicing physician, health care provider, or researcher, or engaged in the pharmaceutical industry or in clinical trial design, recent advances in our understanding of the natural history of MS are of key significance.